Digital Commons Network^™

Endothelial Adam10 Utilization Defines A Molecular Pathway Of Vascular Injury In Mice With Bacterial Sepsis, Danielle N. Alfano, Mark J. Miller, Juliane Bubeck-Wardenburg

2020-Current year OA Pubs

The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial ADAM10 was essential for the pathogenesis of Staphylococcus aureus sepsis, contributing to α-toxin-mediated (Hla-mediated) microvascular thrombus formation and lethality. As ADAM10 is essential for endothelial development and homeostasis, we examined whether other major human sepsis pathogens also rely on ADAM10-dependent pathways in …

Survival Of Veterans Treated With Enzalutamide And Abiraterone For Metastatic Castrate Resistant Prostate Cancer Based On Comorbid Diseases, Martin W Schoen, Kenneth R Carson, Seth A Eisen, Charles L Bennett, Suhong Luo, Melissa A Reimers, Eric M Knoche, Alison L Whitmer, Yan Yan, Bettina F Drake, Kristen M Sanfilippo

2020-Current year OA Pubs

BACKGROUND: Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions.

METHODS: Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between …

Myeloid Lineage Switch Following Cd7-Targeted Chimeric Antigen Receptor T-Cell Therapy In Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia, Ibrahim Aldoss, David Spencer, Et Al.

2020-Current year OA Pubs

No abstract provided.

Lasofoxifene Versus Fulvestrant For Er+/Her2- Metastatic Breast Cancer With An Esr1 Mutation: Results From The Randomized, Phase Ii Elaine 1 Trial, M P Goetz, N A Bagegni, Et Al.

2020-Current year OA Pubs

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts.

PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, …

Phase 1/1b Open-Label, Dose-Escalation Study Of Fruquintinib In Patients With Advanced Solid Tumors In The United States, Andrea Wang-Gillam, William Schelman, Stacey Ukrainskyj, Caly Chien, Martha Gonzalez, Zhao Yang, Marek Kania, Heather Yeckes-Rodin

2020-Current year OA Pubs

This open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples …

Trpv4 Differentially Controls Inflammatory Cytokine Networks During Static And Dynamic Compression Of The Intervertebral Disc, Garrett W D Easson, Alireza Savadipour, Christian Gonzalez, Farshid Guilak, Simon Y Tang

2020-Current year OA Pubs

BACKGROUND: The ion channel transient receptor potential vanilloid 4 (TRPV4) critically transduces mechanical forces in the IVD, and its inhibition can prevent IVD degeneration due to static overloading. However, it remains unknown whether different modes of loading signals through TRPV4 to regulate the expression of inflammatory cytokines. We hypothesized that TRPV4 signaling is essential during static and dynamic loading to mediate homeostasis and mechanotransduction.

METHODS: Mouse functional spine units were isolated and either cyclically compressed for 5 days (1 Hz, 1 h, 10% strain) or statically compressed (24 h, 0.2 MPa). Conditioned media were monitored at 6 h, 24 h, …

Greater Socioenvironmental Risk Factors And Higher Chronic Pain Stage Are Associated With Thinner Bilateral Temporal Lobes, Lisa H Antoine, Burel R Goodin, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Previous research indicates ethnic/race group differences in pain and neurodegenerative diseases. Accounting for socioenvironmental factors reduces ethnic/race group differences in clinical and experimental pain. In the current study sample, we previously reported that in individuals with knee pain, ethnic/race group differences were observed in bilateral temporal lobe thickness, areas of the brain associated with risk for Alzheimer's disease, and related dementias. The purpose of the study was to determine if socioenvironmental factors reduce or account for previously observed ethnic/race group differences and explore if a combined effect of socioenvironmental risk and chronic pain severity on temporal lobe cortices is …

Blockade Of Il-6r Prevents Preterm Birth And Adverse Neonatal Outcomes, Marcelo Farias-Jofre, Valeria Garcia-Flores, Nardhy Gomez-Lopez, Et Al.

2020-Current year OA Pubs

BACKGROUND: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.

METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment …

Progressive, Edematous Plaques, Mild Pancytopenia, And Inflammation, Leigh A Compton, Heather A Jones, Connor A Vinyard, Yi-Shan Lee, Matthew J Walter, Christine C Yokoyama

2020-Current year OA Pubs

No abstract provided.

Risk Profiles And Incidence Of Cardiovascular Events Across Different Cancer Types, J D Mitchell, M Laurie, Q Xia, B Dreyfus, N Jain, A Jain, D Lane, D J Lenihan

2020-Current year OA Pubs

BACKGROUND: Cancer survivors are at increased risk for cardiovascular (CV) disease, although additional data are needed to better understand the incidence of CV events across different malignancies. This study sought to characterize the incidence of major adverse CV events [myocardial infarction, stroke, unstable angina (MACE), or heart failure (HF)] across multiple cancer types after cancer diagnosis.

PATIENTS AND METHODS: Patients were identified from a USA-based administrative claims database who had index cancer diagnoses of breast, lung, prostate, melanoma, myeloma, kidney, colorectal, leukemia, or lymphoma between 2011 and 2019, with continuous enrollment for ≥12 months before diagnosis. Baseline CV risk factors …

Camkk2 And Chk1 Phosphorylate Human Stn1 In Response To Replication Stress To Protect Stalled Forks From Aberrant Resection, Rishi Kumar Jaiswal, Kai-Hang Lei, Megan Chastain, Yuan Wang, Olga Shiva, Shan Li, Zhongsheng You, Peter Chi, Weihang Chai

2020-Current year OA Pubs

Keeping replication fork stable is essential for safeguarding genome integrity; hence, its protection is highly regulated. The CTC1-STN1-TEN1 (CST) complex protects stalled forks from aberrant MRE11-mediated nascent strand DNA degradation (NSD). However, the activation mechanism for CST at forks is unknown. Here, we report that STN1 is phosphorylated in its intrinsic disordered region. Loss of STN1 phosphorylation reduces the replication stress-induced STN1 localization to stalled forks, elevates NSD, increases MRE11 access to stalled forks, and decreases RAD51 localization at forks, leading to increased genome instability under perturbed DNA replication condition. STN1 is phosphorylated by both the ATR-CHK1 and the calcium-sensing …

Intravenous Levothyroxine For Unstable Brain-Dead Heart Donors, Rajat Dhar, Gary F Marklin, W Dean Klinkenberg, Jinli Wang, Charles W Goss, Abhijit V Lele, Clark D Kensinger, Paul A Lange, Daniel J Lebovitz

2020-Current year OA Pubs

BACKGROUND: Hemodynamic instability and myocardial dysfunction are major factors preventing the transplantation of hearts from organ donors after brain death. Intravenous levothyroxine is widely used in donor care, on the basis of observational data suggesting that more organs may be transplanted from donors who receive hormonal supplementation.

METHODS: In this trial involving 15 organ-procurement organizations in the United States, we randomly assigned hemodynamically unstable potential heart donors within 24 hours after declaration of death according to neurologic criteria to open-label infusion of intravenous levothyroxine (30 μg per hour for a minimum of 12 hours) or saline placebo. The primary outcome …

Clinical Situations For Which 3d Printing Is Considered An Appropriate Representation Or Extension Of Data Contained In A Medical Imaging Examination: Vascular Conditions, Joonhyuk Lee, Seetharam C Chadalavada, Anish Ghodadra, Arafat Ali, Elsa M Arribas, Leonid Chepelev, Ciprian N Ionita, Prashanth Ravi, Justin R Ryan, Lumarie Santiago, Nicole Wake, Adnan M Sheikh, Frank J Rybicki, David H Ballard

2020-Current year OA Pubs

BACKGROUND: Medical three-dimensional (3D) printing has demonstrated utility and value in anatomic models for vascular conditions. A writing group composed of the Radiological Society of North America (RSNA) Special Interest Group on 3D Printing (3DPSIG) provides appropriateness recommendations for vascular 3D printing indications.

METHODS: A structured literature search was conducted to identify all relevant articles using 3D printing technology associated with vascular indications. Each study was vetted by the authors and strength of evidence was assessed according to published appropriateness ratings.

RESULTS: Evidence-based recommendations for when 3D printing is appropriate are provided for the following areas: aneurysm, dissection, extremity vascular …

A Youth-Centred Approach To Improving Engagement In Hiv Services: Human-Centred Design Methods And Outcomes In A Research Trial In Kisumu County, Kenya, Eliud Omondi Akama, Thomas Odeny, Ingrid Eshun-Wilson, Elvin H Geng, Et Al.

2020-Current year OA Pubs

UNLABELLED: IntroductionInnovative interventions are needed to improve HIV outcomes among adolescents and young adults (AYAs) living with HIV. Engaging AYAs in intervention development could increase effectiveness and youth acceptance, yet research is limited. We applied human-centred design (HCD) to refine adherence-support interventions pretrial and assessed HCD workshop acceptability.

METHODS: We applied an iterative, four-phased HCD process in Kenya that included: (1) systematic review of extant knowledge, (2) prioritisation of design challenges, (3) a co-creation workshop and (4) translation tables to pair insights with trial intervention adaptations. The co-creation workshop was co-led by youth facilitators employing participatory activities to inform intervention …

Functional Analysis Of Recurrent Cdc20 Promoter Variants In Human Melanoma, Paula M Godoy, Abimbola Oyedeji, Jacqueline L Mudd, Vasilios A Morikis, Anna P Zarov, Gregory D Longmore, Ryan C Fields, Charles K Kaufman

2020-Current year OA Pubs

Small nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, …

Blobcut: A Contrastive Learning Method To Support Small Blob Detection In Medical Imaging, Teng Li, Yanzhe Xu, Teresa Wu, Jennifer R Charlton, Kevin M Bennett, Firas Al-Hindawi

2020-Current year OA Pubs

Medical imaging-based biomarkers derived from small objects (e.g., cell nuclei) play a crucial role in medical applications. However, detecting and segmenting small objects (a.k.a. blobs) remains a challenging task. In this research, we propose a novel 3D small blob detector called BlobCUT. BlobCUT is an unpaired image-to-image (I2I) translation model that falls under the Contrastive Unpaired Translation paradigm. It employs a blob synthesis module to generate synthetic 3D blobs with corresponding masks. This is incorporated into the iterative model training as the ground truth. The I2I translation process is designed with two constraints: (1) a convexity consistency constraint that relies …

Relationship Between The Covid-19 Pandemic And Structural Inequalities Within The Pediatric Trauma Population, Christina Georgeades, Martin S Keller, Et Al.

2020-Current year OA Pubs

BACKGROUND: The COVID-19 pandemic disrupted social, political, and economic life across the world, shining a light on the vulnerability of many communities. The objective of this study was to assess injury patterns before and after implementation of stay-at-home orders (SHOs) between White children and children of color and across varying levels of vulnerability based upon children's home residence.

METHODS: A multi-institutional retrospective study was conducted evaluating patients < 18 years with traumatic injuries. A "Control" cohort from an averaged March-September 2016-2019 time period was compared to patients injured after SHO initiation-September 2020 ("COVID" cohort). Interactions between race/ethnicity or social vulnerability index (SVI), a marker of neighborhood vulnerability and socioeconomic status, and the COVID-19 timeframe with regard to the outcomes of interest were assessed using likelihood ratio Chi-square tests. Differences in injury intent, type, and mechanism were then stratified and explored by race/ethnicity and SVI separately.

RESULTS: A total of 47,385 patients met study inclusion. Significant interactions existed between race/ethnicity and the COVID-19 SHO period for intent (p < 0.001) and mechanism of injury (p < 0.001). There was also significant interaction between SVI and the COVID-19 SHO period for mechanism of injury (p = 0.01). Children of color experienced a significant increase in intentional (COVID 16.4% vs. Control 13.7%, p = 0.03) and firearm (COVID 9.0% vs. Control 5.2%, p < 0.001) injuries, but no change was seen among White children. Children from the most vulnerable neighborhoods suffered an increase in firearm injuries (COVID 11.1% vs. Control 6.1%, p = 0.001) with children from the least vulnerable neighborhoods having no change. All-terrain vehicle (ATV) and bicycle crashes increased for children of color (COVID 2.0% vs. Control 1.1%, p = 0.04 for ATV; COVID 6.7% vs. Control 4.8%, p = 0.02 for bicycle) and White children (COVID 9.6% vs. Control 6.2%, p < 0.001 for ATV; COVID 8.8% vs. Control 5.8%, p < 0.001 for bicycle).

CONCLUSIONS: In contrast to White children and children from neighborhoods of …

Sex-Associated Differences In Frequencies And Prognostic Impact Of Recurrent Genetic Alterations In Adult Acute Myeloid Leukemia (Alliance, Amlcg), Michael Ozga, Geoffrey L Uy, Et Al.

2020-Current year OA Pubs

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal …

Impact Of Circulating Lymphoma Cells At Diagnosis On Outcomes In Patients With Marginal Zone Lymphoma: A Multicenter Cohort Study, Kaitlin Annunzio, Marcus P Watkins, Nancy L Bartlett, Et Al.

2020-Current year OA Pubs

No abstract provided.

Clinical Situations For Which 3d Printing Is Considered An Appropriate Representation Or Extension Of Data Contained In A Medical Imaging Examination: Neurosurgical And Otolaryngologic Conditions, Arafat Ali, Jonathan M Morris, Summer J Decker, Yu-Hui Huang, Nicole Wake, Frank J Rybicki, David H Ballard

2020-Current year OA Pubs

BACKGROUND: Medical three dimensional (3D) printing is performed for neurosurgical and otolaryngologic conditions, but without evidence-based guidance on clinical appropriateness. A writing group composed of the Radiological Society of North America (RSNA) Special Interest Group on 3D Printing (SIG) provides appropriateness recommendations for neurologic 3D printing conditions.

METHODS: A structured literature search was conducted to identify all relevant articles using 3D printing technology associated with neurologic and otolaryngologic conditions. Each study was vetted by the authors and strength of evidence was assessed according to published guidelines.

RESULTS: Evidence-based recommendations for when 3D printing is appropriate are provided for diseases of …

Essential Content For Teaching Implementation Practice In Healthcare: A Mixed-Methods Study Of Teams Offering Capacity-Building Initiatives, Jessica Reszel, Beth E Crowner, Et Al.

2020-Current year OA Pubs

BACKGROUND: Applying the knowledge gained through implementation science can support the uptake of research evidence into practice; however, those doing and supporting implementation (implementation practitioners) may face barriers to applying implementation science in their work. One strategy to enhance individuals' and teams' ability to apply implementation science in practice is through training and professional development opportunities (capacity-building initiatives). Although there is an increasing demand for and offerings of implementation practice capacity-building initiatives, there is no universal agreement on what content should be included. In this study we aimed to explore what capacity-building developers and deliverers identify as essential training content …

Formative Evaluation And Adaptation Of A Hypertension Extension For Community Health Outcomes Program For Healthcare Workers Within The Federal Capital Territory, Nigeria, Abigail S Baldridge, Nadia Goldstar, Grace C Bellinger, Abigail T Denoma, Ikechukwu A Orji, Gabriel L Shedul, Rosemary C B Okoli, Nanna R Ripiye, Adaora Odukwe, Olabisi Dabiri, L Nneka Mobisson, Dike B Ojji, Mark D Huffman, Namratha R Kandula, Lisa R Hirschhorn

2020-Current year OA Pubs

BACKGROUND: The Extension for Community Health Outcomes (ECHO) model has been used extensively to link care providers in rural communities with experts with the aim of improving local patient care.

OBJECTIVE: The aim of this qualitative research study was to assess the feasibility, acceptability, perceived needs, and contextual factors to guide implementation of a hypertension focused ECHO program for Community Health Extension Workers (CHEWs) in the Federal Capital Territory, Nigeria.

METHODS: From September 2020 to December 2020, key informant interviews were performed with seven global organizations (hubs) providing ECHO training focused on cardiovascular disease or nephrology to identify contextual factors …

Single-Cell Multiomics Of The Human Retina Reveals Hierarchical Transcription Factor Collaboration In Mediating Cell Type-Specific Effects Of Genetic Variants On Gene Regulation, Jun Wang, Xuesen Cheng, Qingnan Liang, Leah A Owen, Jiaxiong Lu, Yiqiao Zheng, Meng Wang, Shiming Chen, Margaret M Deangelis, Yumei Li, Rui Chen

2020-Current year OA Pubs

BACKGROUND: Systematic characterization of how genetic variation modulates gene regulation in a cell type-specific context is essential for understanding complex traits. To address this question, we profile gene expression and chromatin accessibility in cells from healthy retinae of 20 human donors through single-cell multiomics and genomic sequencing.

RESULTS: We map eQTL, caQTL, allelic-specific expression, and allelic-specific chromatin accessibility in major retinal cell types. By integrating these results, we identify and characterize regulatory elements and genetic variants effective on gene regulation in individual cell types. The majority of identified sc-eQTLs and sc-caQTLs display cell type-specific effects, while the cis-elements containing genetic …

Awareness With Paralysis And Symptoms Of Post-Traumatic Stress Disorder Among Mechanically Ventilated Emergency Department Survivors (Ed-Awareness-2 Trial): Study Protocol For A Pragmatic, Multicenter, Stepped Wedge Cluster Randomized Trial, Brian M Fuller, Brian E Driver, Michael B Roberts, Christa A Schorr, Kathryn Thompson, Brett Faine, Julianne Yeary, Nicholas M Mohr, Ryan D Pappal, Robert J Stephens, Yan Yan, Nicholas J Johnson, Brian W Roberts

2020-Current year OA Pubs

BACKGROUND: Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1-0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3-7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a …

Association Between The Introduction Of A National Targeted Intervention Program And The Incidence Of Surgical Site Infections In Swiss Acute Care Hospitals, Marcus Eder, Rami Sommerstein, Arlette Szelecsenyi, Alexander Schweiger, Matthias Schlegel, Andrew Atkinson, Stefan P Kuster, Danielle Vuichard-Gysin, Nicolas Troillet, Andreas F Widmer, For Swissnoso

2020-Current year OA Pubs

BACKGROUND: In Switzerland, the national surgical site infection (SSI) surveillance program showed a modest decrease in SSI rates for different procedures over the last decade. The study aimed to determine whether a multimodal, targeted intervention program in addition to existing SSI surveillance is associated with decreased SSI rates in the participating hospitals.

METHODS: Prospective multicenter pre- and postintervention study conducted in eight Swiss acute care hospitals between 2013 and 2020. All consecutive patients > 18 years undergoing cardiac, colon, or hip/knee replacement surgery were included. The follow-up period was 30 days and one year for implant-related surgery. Patients with at least …

Evaluating 17 Methods Incorporating Biological Function With Gwas Summary Statistics To Accelerate Discovery Demonstrates A Tradeoff Between High Sensitivity And High Positive Predictive Value, Amy Moore, Jesse A Marks, Bryan C Quach, Yuelong Guo, Laura J Bierut, Nathan C Gaddis, Dana B Hancock, Grier P Page, Eric O Johnson

2020-Current year OA Pubs

Where sufficiently large genome-wide association study (GWAS) samples are not currently available or feasible, methods that leverage increasing knowledge of the biological function of variants may illuminate discoveries without increasing sample size. We comprehensively evaluated 17 functional weighting methods for identifying novel associations. We assessed the performance of these methods using published results from multiple GWAS waves across each of five complex traits. Although no method achieved both high sensitivity and positive predictive value (PPV) for any trait, a subset of methods utilizing pleiotropy and expression quantitative trait loci nominated variants with high PPV (>75%) for multiple traits. Application …

Genetic Separation Of Brca1 Functions Reveal Mutation-Dependent Polθ Vulnerabilities, John J Krais, Et Al.

2020-Current year OA Pubs

Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq

Dynamical Control Enables The Formation Of Demixed Biomolecular Condensates, Andrew Z Lin, Kiersten M Ruff, Furqan Dar, Ameya Jalihal, Matthew R King, Jared M Lalmansingh, Ammon E Posey, Nadia A Erkamp, Ian Seim, Amy S Gladfelter, Rohit V Pappu

2020-Current year OA Pubs

Cellular matter can be organized into compositionally distinct biomolecular condensates. For example, in Ashbya gossypii, the RNA-binding protein Whi3 forms distinct condensates with different RNA molecules. Using criteria derived from a physical framework for explaining how compositionally distinct condensates can form spontaneously via thermodynamic considerations, we find that condensates in vitro form mainly via heterotypic interactions in binary mixtures of Whi3 and RNA. However, within these condensates, RNA molecules become dynamically arrested. As a result, in ternary systems, simultaneous additions of Whi3 and pairs of distinct RNA molecules lead to well-mixed condensates, whereas delayed addition of an RNA component results …

Heterogeneous Cardiac Sympathetic Innervation Gradients Promote Arrhythmogenesis In Murine Dilated Cardiomyopathy, Al-Hassan J Dajani, Carla Valenzuela-Ripoll, Ali Javaheri, Et Al.

2020-Current year OA Pubs

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve …

Stratification Of Risk For Emergent Intracranial Abnormalities In Children With Headaches: A Pediatric Emergency Care Applied Research Network (Pecarn) Study Protocol, Daniel S Tsze, Kimberly S Quayle, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Headache is a common chief complaint of children presenting to emergency departments (EDs). Approximately 0.5%-1% will have emergent intracranial abnormalities (EIAs) such as brain tumours or strokes. However, more than one-third undergo emergent neuroimaging in the ED, resulting in a large number of children unnecessarily exposed to radiation. The overuse of neuroimaging in children with headaches in the ED is driven by clinician concern for life-threatening EIAs and lack of clarity regarding which clinical characteristics accurately identify children with EIAs. The study objective is to derive and internally validate a stratification model that accurately identifies the risk of EIA …