Digital Commons Network^™

Clustering Of Aromatic Residues In Prion-Like Domains Can Tune The Formation, State, And Organization Of Biomolecular Condensates, Alex S Holehouse, Garrett M Ginell, Daniel Griffith, Elvan Böke

2020-Current year OA Pubs

In immature oocytes, Balbiani bodies are conserved membraneless condensates implicated in oocyte polarization, the organization of mitochondria, and long-term organelle and RNA storage. In

Identification Of Disease-Linked Hyperactivating Mutations In Ube3a Through Large-Scale Functional Variant Analysis, Kellan P Weston, Xiaoyi Gao, Jinghan Zhao, Kwang-Soo Kim, Susan E Maloney, Jill Gotoff, Sumit Parikh, Yen-Chen Leu, Kuen-Phon Wu, Marwan Shinawi, Joshua P Steimel, Joseph S Harrison, Jason J Yi

Open Access Publications

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site …

Visual Prototypes In The Ventral Stream Are Attuned To Complexity And Gaze Behavior, Olivia Rose, James Johnson, Binxu Wang, Carlos R Ponce

Open Access Publications

Early theories of efficient coding suggested the visual system could compress the world by learning to represent features where information was concentrated, such as contours. This view was validated by the discovery that neurons in posterior visual cortex respond to edges and curvature. Still, it remains unclear what other information-rich features are encoded by neurons in more anterior cortical regions (e.g., inferotemporal cortex). Here, we use a generative deep neural network to synthesize images guided by neuronal responses from across the visuocortical hierarchy, using floating microelectrode arrays in areas V1, V4 and inferotemporal cortex of two macaque monkeys. We hypothesize …

Dasatinib And Dexamethasone Followed By Hematopoietic Cell Transplantation For Adults With Ph-Positive All, Matthew J. Wieduwilt, Geoffrey L. Uy, Et Al

Open Access Publications

No abstract provided.

Optimization Of Non-Coding Regions For A Non-Modified Mrna Covid-19 Vaccine, Makda S Gebre, Susanne Rauch, Adrianus C M Boon, Et Al

Open Access Publications

The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans

Dual Lactate Clearance In The Viability Assessment Of Livers Donated After Circulatory Death With Ex Situ Normothermic Machine Perfusion, Min Xu, Fangyu Zhou, Ola Ahmed, Lucy V Randle, Jun-Kyu Shin, Yuehui Zhu, Gundumi A Upadhya, Kathleen Byrnes, Brian Wong, Jae-Sung Kim, Yiing Lin, William C Chapman

Open Access Publications

Perfusate lactate clearance (LC) is considered one of the useful indicators of liver viability assessment during normothermic machine perfusion (NMP); however, the applicable scope and potential mechanisms of LC remain poorly defined in the setting of liver donation after circulatory death.

Methods: The ex situ NMP of end-ischemic human livers was performed using the OrganOx Metra device. We further studied the extracellular signal-regulated kinases (phospho-extracellular signal-regulated kinase1/2 [pERK1/2]) pathway and several clinical parameters of these livers with successful LC (sLC, n = 5) compared with non-sLC (nLC, n = 5) in the perfusate (<2.2 mmol/L at 2 h, n = 5, rapid retrieval without normothermic regional perfusion).

Results: We found the pERK1/2 level …

Development And Immunogenicity Of A Prototype Multivalent Group B Streptococcus Bioconjugate Vaccine, Jeremy A Duke, Amy V Paschall, Lloyd S Robinson, Cory J Knoot, Evgeny Vinogradov, Nichollas E Scott, Mario F Feldman, Fikri Y Avci, Christian M Harding

2020-Current year OA Pubs

Group B

Angiotensin Receptor-Neprilysin Inhibition In Acute Myocardial Infarction, Marc A Pfeffer, Douglas L Mann, Et Al

Open Access Publications

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.

METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident …

Estradiol Protects Against Noise-Induced Hearing Loss And Modulates Auditory Physiology In Female Mice, Benjamine Shuster, Ryan Casserly, Erika Lipford, Rafal Olszewski, Beatrice Milon, Shaun Viechweg, Kanisa Davidson, Jennifer Enoch, Mark Mcmurray, Mark A. Rutherford, Kevin K. Ohlemiller, Michael Hoa, Didier A. Depireux, Jessica A. Mong, Ronna Hertzano

Open Access Publications

No abstract provided.

Matched Cohort Study Of Germline Brca Mutation Carriers With Triple Negative Breast Cancer In Brightness, Otto Metzger-Filho, Katharine Collier, Sarah Asad, Mark Watson, Et Al

Open Access Publications

No abstract provided.

Cognitive Deficits And Impaired Hippocampal Long-Term Potentiation In K Atp-Induced Dend Syndrome, Shaul Yahil, David F Wozniak, Zihan Yan, Steven Mennerick, Maria S Remedi

Open Access Publications

ATP-sensitive potassium (K

Using Postmarket Surveillance To Assess Safety-Related Events In A Digital Rehabilitation App (Kaia App): Observational Study, Deeptee Jain, Kevin Norman, Zachary Werner, Bar Makovoz, Turner Baker, Stephan Huber

Open Access Publications

BACKGROUND: Low back pain (LBP) affects nearly 4 out of 5 individuals during their lifetime and is the leading cause of disability globally. Digital therapeutics are emerging as effective treatment options for individuals experiencing LBP. Despite the growth of evidence demonstrating the benefits of these therapeutics in reducing LBP and improving functional outcomes, little data has been systematically collected on their safety profiles.

OBJECTIVE: This study aims to evaluate the safety profile of a multidisciplinary digital therapeutic for LBP, the Kaia App, by performing a comprehensive assessment of reported adverse events (AEs) by users as captured by a standardized process …

Synaptic Zn 2+ Potentiates The Effects Of Cocaine On Striatal Dopamine Neurotransmission And Behavior, Juan L. Gomez, Marco Pignatelli, Et Al

Open Access Publications

No abstract provided.

A Whole Genome Duplication Drives The Genome Evolution Of Phytophthora Betacei, A Closely Related Species To Phytophthora Infestans, David A Ayala-Usma, Martha Cárdenas, Romain Guyot, Maryam Chaib De Mares, Adriana Bernal, Alejandro Reyes Muñoz, Silvia Restrepo

2020-Current year OA Pubs

BACKGROUND: Pathogens of the genus Phytophthora are the etiological agents of many devastating diseases in several high-value crops and forestry species such as potato, tomato, cocoa, and oak, among many others. Phytophthora betacei is a recently described species that causes late blight almost exclusively in tree tomatoes, and it is closely related to Phytophthora infestans that causes the disease in potato crops and other Solanaceae. This study reports the assembly and annotation of the genomes of P. betacei P8084, the first of its species, and P. infestans RC1-10, a Colombian strain from the EC-1 lineage, using long-read SMRT sequencing technology. …

Staphylococcus Aureus Injection Drug Use-Associated Bloodstream Infections Are Propagated By Community Outbreaks Of Diverse Lineages, Laura R Marks, Juan J Calix, John A Wildenthal, Meghan A Wallace, Sanjam S Sawhney, Eric M Ransom, Michael J Durkin, Jeffrey P Henderson, Carey-Ann D Burnham, Gautam Dantas

Open Access Publications

Background: The ongoing injection drug use (IDU) crisis in the United States has been complicated by an emerging epidemic of

Methods: We performed a case-control study comparing

Results: Here we show that patients with IDU-BSI experience longer durations of bacteremia and have lower medical therapy completion rates. In phylogenetic analyses, 45/154 and 1/91 contemporaneous IDU-BSI and non-IDU BSI staphylococcal isolates, respectively, group into multiple, unique clonal clusters, revealing that pathogen community transmission distinctively spurs IDU-BSI. Lastly, multiple

Conclusions: We identify clonal expansion of multiple

Competitive Binding Of E3 Ligases Trim26 And Wwp2 Controls Sox2 In Glioblastoma, Tatenda Mahlokozera, Bhuvic Patel, Hao Chen, Patrick Desouza, Xuan Qu, Diane D Mao, Daniel Hafez, Wei Yang, Rukayat Taiwo, Mounica Paturu, Afshin Salehi, Amit D Gujar, Gavin P Dunn, Nima Mosammaparast, Allegra A Petti, Hiroko Yano, Albert H Kim

2020-Current year OA Pubs

The pluripotency transcription factor SOX2 is essential for the maintenance of glioblastoma stem cells (GSC), which are thought to underlie tumor growth, treatment resistance, and recurrence. To understand how SOX2 is regulated in GSCs, we utilized a proteomic approach and identified the E3 ubiquitin ligase TRIM26 as a direct SOX2-interacting protein. Unexpectedly, we found TRIM26 depletion decreased SOX2 protein levels and increased SOX2 polyubiquitination in patient-derived GSCs, suggesting TRIM26 promotes SOX2 protein stability. Accordingly, TRIM26 knockdown disrupted the SOX2 gene network and inhibited both self-renewal capacity as well as in vivo tumorigenicity in multiple GSC lines. Mechanistically, we found TRIM26, …

Influential Periods In Longitudinal Clinical Cardiovascular Health Scores, Amy E Krefman, Vito M R Muggeo, Et Al.

2020-Current year OA Pubs

The prevalence of ideal cardiovascular health (CVH) among adults in the United States is low and decreases with age. Our objective was to identify specific age windows when the loss of CVH accelerates, to ascertain preventive opportunities for intervention. Data were pooled from 5 longitudinal cohorts (Project Heartbeat!, Cardiovascular Risk in Young Finns Study, The Bogalusa Heart Study, Coronary Artery Risk Development in Young Adults, Special Turku Coronary Risk Factor Intervention Project) from the United States and Finland from 1973 to 2012. Individuals with clinical CVH factors (i.e., body mass index, blood pressure, cholesterol, blood glucose) measured from ages 8 …

Reward Deficiency Syndrome (Rds): A Cytoarchitectural Common Neurobiological Trait Of All Addictions, Kenneth Blum, Abdalla Bowirrat, Eric R Braverman, David Baron, Jean Lud Cadet, Shan Kazmi, Igor Elman, Panyotis K Thanos, Rajendra D Badgaiyan, William B Downs, Debasis Bagchi, Luis Llanos-Gomez, Mark S Gold

2020-Current year OA Pubs

Alcohol and other substance use disorders share comorbidity with other RDS disorders, i.e., a reduction in dopamine signaling within the reward pathway. RDS is a term that connects addictive, obsessive, compulsive, and impulsive behavioral disorders. An estimated 2 million individuals in the United States have opioid use disorder related to prescription opioids. It is estimated that the overall cost of the illegal and legally prescribed opioid crisis exceeds one trillion dollars. Opioid Replacement Therapy is the most common treatment for addictions and other RDS disorders. Even after repeated relapses, patients are repeatedly prescribed the same opioid replacement treatments. A recent …

Cytokine Exposure Mediates Transcriptional Activation Of The Orphan Nuclear Receptor Nur77 In Hematopoietic Cells, Orsola Di Martino, Haixia Niu, Gayla Hadwiger, Margaret A Ferris, John S Welch

Open Access Publications

The orphan nuclear receptor Nur77 is an immediate-early response gene that based on tissue and cell context is implicated in a plethora of cellular processes, including proliferation, differentiation, apoptosis, metabolism, and inflammation. Nur77 has a ligand-binding pocket that is obstructed by hydrophobic side groups. Naturally occurring, cell-endogenous ligands have not been identified, and Nur77 transcriptional activity is thought to be regulated through posttranslational modification and modulation of protein levels. To determine whether Nur77 is transcriptionally active in hematopoietic cells in vivo, we used an upstream activating sequence (UAS)-GFP transgenic reporter. We found that Nur77 is transcriptionally inactive in vivo in …

U2af1 Is A Haplo-Essential Gene Required For Hematopoietic Cancer Cell Survival In Mice, Brian A Wadugu, Sridhar Nonavinkere Srivatsan, Amanda Heard, Michael O Alberti, Matthew Ndonwi, Jie Liu, Sarah Grieb, Joseph Bradley, Jin Shao, Tanzir Ahmed, Cara L Shirai, Ajay Khanna, Christopher A Miller, Matthew J Walter, Et Al

Open Access Publications

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained WT allele is expressed, suggesting that mutant hematopoietic cells may require the residual WT allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knockout mice were similar to those in control mice, but that deletion of the WT allele in U2AF1(S34F) heterozygous mutant-expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of …

8-Azaadenosine And 8-Chloroadenosine Are Not Selective Inhibitors Of Adar, Kyle A Cottrell, Luisangely Soto Torres, Michael G Dizon, Jason D Weber

Open Access Publications

The RNA editing enzyme ADAR, is an attractive therapeutic target for multiple cancers. Through its deaminase activity, ADAR edits adenosine to inosine in dsRNAs. Loss of ADAR in some cancer cell lines causes activation of the type I interferon pathway and the PKR translational repressor, leading to inhibition of proliferation and stimulation of cell death. As such, inhibition of ADAR function is a viable therapeutic strategy for many cancers. However, there are no FDA approved inhibitors of ADAR. Two small molecules have been previously shown to inhibit ADAR or reduce its expression: 8-azaadenosine and 8-chloroadenosine. Here we show that neither …

Phase I Study Of Single Agent Niz985, A Recombinant Heterodimeric Il-15 Agonist, In Adult Patients With Metastatic Or Unresectable Solid Tumors, Kevin Conlon, Andrea Wang-Gillam, Et Al

2020-Current year OA Pubs

BACKGROUND: NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors.

METHODS: Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, …

Tai Chi For Cancer Survivors: A Systematic Review Toward Consensus-Based Guidelines, Lin Yang, Kerri Winters-Stone, Benny Rana, Chao Cao, Linda E Carlson, Kerry S Courneya, Christine M Friedenreich, Kathryn H Schmitz

Open Access Publications

To manage acute, long-term, and late effects of cancer, current guidelines recommend moderate-to-vigorous intensity aerobic and resistance exercise. Unfortunately, not all cancer survivors are able or willing to perform higher intensity exercise during difficult cancer treatments or because of other existing health conditions. Tai Chi is an equipment-free, multicomponent mind-body exercise performed at light-to-moderate intensity that may provide a more feasible alternative to traditional exercise programs for some cancer survivors. This systematic review evaluated the therapeutic efficacy of Tai Chi across the cancer care continuum. We searched MEDLINE/PubMed, Embase, SCOPUS, and CINAHL databases for interventional studies from inception to 18 …

Diagnostics To Support Elimination Of Lymphatic Filariasis-Development Of Two Target Product Profiles, Kimberly Y. Won, Gary J. Weil, Et Al

Open Access Publications

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs …

Cardiac Myosin Contraction And Mechanotransduction In Health And Disease, Samantha K Barrick, Michael J Greenberg

Open Access Publications

Cardiac myosin is the molecular motor that powers heart contraction by converting chemical energy from ATP hydrolysis into mechanical force. The power output of the heart is tightly regulated to meet the physiological needs of the body. Recent multiscale studies spanning from molecules to tissues have revealed complex regulatory mechanisms that fine-tune cardiac contraction, in which myosin not only generates power output but also plays an active role in its regulation. Thus, myosin is both shaped by and actively involved in shaping its mechanical environment. Moreover, these studies have shown that cardiac myosin-generated tension affects physiological processes beyond muscle contraction. …

Cardiac Stereotactic Ablative Radiotherapy For Control Of Refractory Ventricular Tachycardia: Initial Uk Multicentre Experience, Justin Lee, Clifford Robinson, Phillip Cuculich, Geoffrey Hugo, Et Al

Open Access Publications

BACKGROUND: Options for patients with ventricular tachycardia (VT) refractory to antiarrhythmic drugs and/or catheter ablation remain limited. Stereotactic radiotherapy has been described as a novel treatment option.

METHODS: Seven patients with recurrent refractory VT, deemed high risk for either first time or redo invasive catheter ablation, were treated across three UK centres with non-invasive cardiac stereotactic ablative radiotherapy (SABR). Prior catheter ablation data and non-invasive mapping were combined with cross-sectional imaging to generate radiotherapy plans with aim to deliver a single 25 Gy treatment. Shared planning and treatment guidelines and prospective peer review were used.

RESULTS: Acute suppression of VT …

Biofilm Formation And Virulence Of Shigella Flexneri Are Modulated By Ph Of Gastrointestinal Tract, I-Ling Chiang, Yi Wang, Satoru Fujii, Brian D Muegge, Qiuhe Lu, Phillip I Tarr, Thaddeus S Stappenbeck

Open Access Publications

No abstract provided.

Genome-Wide Association Study Of Problematic Opioid Prescription Use In 132,113 23andme Research Participants Of European Ancestry, Sandra Sanchez-Roige, Pierre Fontanillas, Mariela V Jennings, Sevim B Bianchi, Yuye Huang, Alexander S Hatoum, Julia Sealock, Lea K Davis, Sarah L Elson, 23andme Research Team, Abraham A Palmer

2020-Current year OA Pubs

The growing prevalence of opioid use disorder (OUD) constitutes an urgent health crisis. Ample evidence indicates that risk for OUD is heritable. As a surrogate (or proxy) for OUD, we explored the genetic basis of using prescription opioids 'not as prescribed'. We hypothesized that misuse of opiates might be a heritable risk factor for OUD. To test this hypothesis, we performed a genome-wide association study (GWAS) of problematic opioid use (POU) in 23andMe research participants of European ancestry (N = 132,113; 21% cases). We identified two genome-wide significant loci (rs3791033, an intronic variant of KDM4A; rs640561, an intergenic variant near …

Approaches To Treat Sensorineural Hearing Loss By Hair-Cell Regeneration: The Current State Of Therapeutic Developments And Their Potential Impact On Audiological Clinical Practice, Ashley S. Hinton, Aizhen Yang-Hood, Angela D. Schrader, Christopher Loose, Kevin K. Ohlemiller, Will J. Mclean

2020-Current year OA Pubs

Sensorineural hearing loss (SNHL) is typically a permanent and often progressive condition that is commonly attributed to sensory cell loss. All vertebrates except mammals can regenerate lost sensory cells. Thus, SNHL is currently only treated with hearing aids or cochlear implants. There has been extensive research to understand how regeneration occurs in nonmammals, how hair cells form during development, and what limits regeneration in maturing mammals. These studies motivated efforts to identify therapeutic interventions to regenerate hair cells as a treatment for hearing loss, with a focus on targeting supporting cells to form new sensory hair cells. The approaches include …

Oncogenic Kras-Induced Feedback Inflammatory Signaling In Pancreatic Cancer: An Overview And New Therapeutic Opportunities, Sapana Bansod, Paarth B Dodhiawala, Kian-Huat Lim

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the