Digital Commons Network^™

Fk506-Binding Protein-Like And Fk506-Binding Protein 8 Regulate Dual Leucine Zipper Kinase Degradation And Neuronal Responses To Axon Injury, Bohm Lee, Yeonsoo Oh, Eunhye Cho, Aaron Diantonio, Valeria Cavalli, Jung Eun Shin, Hae Woong Choi, Yongcheol Cho

Open Access Publications

The dual leucine zipper kinase (DLK) is a key regulator of axon regeneration and degeneration in response to neuronal injury; however, regulatory mechanisms of the DLK function via its interacting proteins are largely unknown. To better understand the molecular mechanism of DLK function, we performed yeast two-hybrid screening analysis and identified FK506-binding protein-like (FKBPL, also known as WAF-1/CIP1 stabilizing protein 39) as a DLK-binding protein. FKBPL binds to the kinase domain of DLK and inhibits its kinase activity. In addition, FKBPL induces DLK protein degradation through ubiquitin-dependent pathways. We further assessed other members in the FKBP protein family and found …

Jagged1/Notch3 Activation Promotes Aortic Hypermuscularization And Stenosis In Elastin Deficiency, Jui M. Dave, Robert Mecham, Et Al

Open Access Publications

Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of …

Commissioning A Secondary Dose Calculation Software For A 0.35 T Mr-Linac, Alex T Price, Nels C Knutson, Taeho Kim, Olga L Green

Open Access Publications

Secondary external dose calculations for a 0.35 T magnetic resonance image-guided radiation therapy (MRgRT) are needed within the radiation oncology community to follow safety standards set forth within the field. We evaluate the commercially available software, RadCalc, in its ability to accurately perform monitor unit dose calculations within a magnetic field. We also evaluate the potential effects of a 0.35 T magnetic field upon point dose calculations. Monitor unit calculations were evaluated with (wMag) and without (noMag) a magnetic field considerations in RadCalc for the ViewRay MRIdian. The magnetic field is indirectly accounted for by using asymmetric profiles for calculation. …

Partial Ablation Of Postsynaptic Dopamine D2 Receptors In The Central Nucleus Of The Amygdala Increases Risk Avoidance In Exploratory Tasks, Eric Casey, María Elena Avale, Alexxai Kravitz, Marcelo Rubinstein

Open Access Publications

The central nucleus of the amygdala (CeA) is involved in the expression of fear and has been implicated in several anxiety disorders. This structure is densely innervated by DAergic projections that impinge on amygdalar neurons expressing various dopamine (DA) receptor subtypes, including D2 receptors (D2Rs). Although various pharmacological approaches have assessed the role of D2Rs in the CeA, the actual participation of postsynaptic D2Rs in the CeA to defensive behaviors remains unclear. Here, we investigated the distribution of D2Rs in the CeA and their role in modifying neuronal activity and fear related behaviors in mice. First, using the mouse reporter …

Translational Randomized Phase Ii Trial Of Cabozantinib In Combination With Nivolumab In Advanced, Recurrent, Or Metastatic Endometrial Cancer, Stephanie Lheureux, Carolyn Mccourt, Et Al

Open Access Publications

BACKGROUND: Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.

PATIENTS AND METHODS: In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was …

Social Isolation And Incident Heart Failure Hospitalization In Older Women: Women's Health Initiative Study Findings, Crystal W Cené, Xiaoyan Iris Leng, Khushnood Faraz, Matthew Allison, Khadijah Breathett, Chloe Bird, Mace Coday, Giselle Corbie-Smith, Randi Foraker, Nkechinyere N Ijioma, Milagros C Rosal, Shawnita Sealy-Jefferson, Tetyana P Shippee, Candyce H Kroenke

Open Access Publications

Background The association of social isolation or lack of social network ties in older adults is unknown. This knowledge gap is important since the risk of heart failure (HF) and social isolation increase with age. The study examines whether social isolation is associated with incident HF in older women, and examines depressive symptoms as a potential mediator and age and race and ethnicity as effect modifiers. Methods and Results This study included 44 174 postmenopausal women of diverse race and ethnicity from the WHI (Women's Health Initiative) study who underwent annual assessment for HF adjudication from baseline enrollment (1993-1998) through …

Transcriptomic Profile Investigations Highlight A Putative Role For Nudt16 In Sepsis, Susie Shih Yin Huang, Darawan Rinchai, Mohammed Toufiq, Basirudeen Syed Ahamed Kabeer, Jessica Roelands, Wouter Hendrickx, Sabri Boughorbel, Davide Bedognetti, Nicholas Van Panhuys, Damien Chaussabel, Mathieu Garand

Open Access Publications

Sepsis is an aberrant systemic inflammatory response mediated by the acute activation of the innate immune system. Neutrophils are important contributors to the innate immune response that controls the infection, but harbour the risk of collateral tissue damage such as thrombosis and organ dysfunction. A better understanding of the modulations of cellular processes in neutrophils and other blood cells during sepsis is needed and can be initiated via transcriptomic profile investigations. To that point, the growing repertoire of publicly accessible transcriptomic datasets serves as a valuable resource for discovering and/or assessing the robustness of biomarkers. We employed systematic literature mining, …

The Degenerative Impact Of Hyperglycemia On The Structure And Mechanics Of Developing Murine Intervertebral Discs, Marianne Lintz, Remy E Walk, Simon Y Tang, Lawrence J Bonassar

2020-Current year OA Pubs

INTRODUCTION: Diabetes has long been implicated as a major risk factor for intervertebral disc (IVD) degeneration, interfering with molecular signaling and matrix biochemistry, which ultimately aggravates the progression of the disease. Glucose content has been previously shown to influence structural and compositional changes in engineered discs in vitro, impeding fiber formation and mechanical stability.

METHODS: In this study, we investigated the impact of diabetic hyperglycemia on young IVDs by assessing biochemical composition, collagen fiber architecture, and mechanical behavior of discs harvested from 3- to 4-month-old db/db mouse caudal spines.

RESULTS: We found that discs taken from diabetic mice with elevated …

Reproducible Brain-Wide Association Studies Require Thousands Of Individuals, Scott Marek, David F Montez, Benjamin P Kay, Alexander S Hatoum, Meghan Rose Donohue, Ryland L Miller, Sridhar Kandala, Dillan J Newbold, Annie Zheng, Nicole A Seider, Andrew N Van, Athanasia Metoki, Timothy O Laumann, Steven E Petersen, Deanna M Barch, Nico U F Dosenbach, Et Al.

2020-Current year OA Pubs

Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions

What Clinical Trials Are Needed For Treatment Of Leiomyosarcoma?, Bernd Kasper, Lorenzo D'Ambrosio, Elizabeth J Davis, Matthew Ingham, Javier Martin Broto, Jonathan C Trent, Winan J Van Houdt, Brian A Van Tine

2020-Current year OA Pubs

Leiomyosarcoma is one of the most common subtypes of soft tissue sarcomas accounting for approximately 20% of sarcomas. As leiomyosarcoma patients frequently develop metastatic disease, effective systemic therapies are needed to improve clinical outcomes. The overall activity of the currently available conventional systemic therapies and the prognosis of patients with advanced and/or metastatic disease are poor. As such, the treatment of this patient population remains challenging. As a result, there is a clear unmet medical need, and designing and performing meaningful clinical studies are of utmost importance to improve the prognosis of this patient group. Therefore, the aim of this …

International Stroke Genetics Consortium Recommendations For Studies Of Genetics Of Stroke Outcome And Recovery, Arne G Lindgren, Jin-Moo Lee, Et Al

2020-Current year OA Pubs

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable …

Pharmacological Chaperones For The Oxytocin Receptor Increase Oxytocin Responsiveness In Myometrial Cells, Manasi Malik, Yingye Fang, Monali Wakle-Prabagaran, Michelle Roh, Kevin Prifti, Antonina I Frolova, Princess I Imoukhuede, Sarah K England

2020-Current year OA Pubs

Oxytocin is a potent uterotonic agent administered to nearly all patients during childbirth in the United States. Inadequate oxytocin response can necessitate Cesarean delivery or lead to uterine atony and postpartum hemorrhage. Thus, it may be clinically useful to identify patients at risk for poor oxytocin response and develop strategies to sensitize the uterus to oxytocin. Previously, we showed that the V281M variant in the oxytocin receptor (OXTR) gene impairs OXTR trafficking to the cell surface, leading to a decreased oxytocin response in cells. Here, we sought to identify pharmacological chaperones that increased oxytocin response in cells expressing WT or …

Enhanced Immunoprecipitation Techniques For The Identification Of Rna-Binding Protein Partners: Igf2bp1 Interactions In Mammary Epithelial Cells, Saja A Fakhraldeen, Scott M Berry, David J Beebe, Avtar Roopra, Celia M Bisbach, Vladimir S Spiegelman, Natalie M Niemi, Caroline M Alexander

2020-Current year OA Pubs

RNA-binding proteins (RBPs) regulate the expression of large cohorts of RNA species to produce programmatic changes in cellular phenotypes. To describe the function of RBPs within a cell, it is key to identify their mRNA-binding partners. This is often done by crosslinking nucleic acids to RBPs, followed by chemical release of the nucleic acid fragments for analysis. However, this methodology is lengthy, which involves complex processing with attendant sample losses, thus large amounts of starting materials and prone to artifacts. To evaluate potential alternative technologies, we tested "exclusion-based" purification of immunoprecipitates (IFAST or SLIDE) and report here that these methods …

Dmp1 Lineage Cells Contribute Significantly To Periosteal Lamellar Bone Formation Induced By Mechanical Loading But Are Depleted From The Bone Surface During Rapid Bone Formation, Taylor L Harris, Matthew J Silva

2020-Current year OA Pubs

Previous work has shown that osteoprogenitor cells (Prx1+) and pre-osteoblasts (Osx+) contribute to mechanical loading-induced bone formation. However, the role of mature Dmp1-expressing osteoblasts has not been reported. In this study we assessed the contribution of osteoblast lineage cells to bone formation at an early time point following mechanical loading (day 8 from onset of loading). We labeled Osx-expressing and Dmp1-expressing cells in inducible Osx and Dmp1 reporter mice (iOsx-Ai9, iDmp1-Ai9), respectively, 3 weeks before loading. Mice were then loaded daily for 5 days (days 1-5) and were dosed with 5-ethynyl-2'-deoxyuridine (EdU) in their drinking water until euthanasia on day …

Sirt1 Selectively Exerts The Metabolic Protective Effects Of Hepatocyte Nicotinamide Phosphoribosyltransferase, Cassandra B Higgins, Allyson L Mayer, Yiming Zhang, Michael Franczyk, Samuel Ballentine, Jun Yoshino, Brian J Debosch

Open Access Publications

Calorie restriction abates aging and cardiometabolic disease by activating metabolic signaling pathways, including nicotinamide adenine dinucleotide (NAD

Synthesis And Structure-Activity Relationship Of Thioacetamide-Triazoles Against Escherichia Coli, Suresh Dharuman, Miranda J Wallace, Stephanie M Reeve, Jürgen B Bulitta, Richard E Lee

Open Access Publications

Infections due to Gram-negative bacteria are increasingly dangerous due to the spread of multi-drug resistant strains, emphasizing the urgent need for new antibiotics with alternative modes of action. We have previously identified a novel class of antibacterial agents, thioacetamide-triazoles, using an antifolate targeted screen and determined their mode of action which is dependent on activation by cysteine synthase A. Herein, we report a detailed examination of the anti-

Labor Induction With Oxytocin In Pregnant Rats Is Not Associated With Oxidative Stress In The Fetal Brain, Tusar Giri, Jia Jiang, Zhiqiang Xu, Ronald Mccarthy, Carmen M Halabi, Eric Tycksen, Alison G Cahill, Sarah K England, Arvind Palanisamy

Open Access Publications

Despite the widespread use of oxytocin for induction of labor, mechanistic insights into fetal/neonatal wellbeing are lacking because of the absence of an animal model that recapitulates modern obstetric practice. Here, we create and validate a hi-fidelity pregnant rat model that mirrors labor induction with oxytocin in laboring women. The model consists of an implantable preprogrammed microprocessor-controlled infusion pump that delivers a gradually escalating dose of intravenous oxytocin to induce birth at term gestation. We validated the model with molecular biological experiments on the uterine myometrium and telemetry-supported assessment of changes in intrauterine pressure. Finally, we applied this model to …

Lipidomics Analysis Of Outer Membrane Vesicles And Elucidation Of The Inositol Phosphoceramide Biosynthetic Pathway In Bacteroides Thetaiotaomicron, Mariana G Sartorio, Ezequiel Valguarnera, Fong-Fu Hsu, Mario F Feldman

Open Access Publications

Approximately one-third of the human colonic microbiome is formed by bacteria from the genus

The Flir Gene Contributes To The Virulence Of S. Marcescens In A Drosophila Intestinal Infection Model, Bechara Sina Rahme, Matthieu Lestradet, Gisela Di Venanzio, Arshad Ayyaz, Miriam Wennida Yamba, Martina Lazzaro, Samuel Liégeois, Eleonora Garcia Véscovi, Dominique Ferrandon

Open Access Publications

Serratia marcescens is an opportunistic bacterium that infects a wide range of hosts including humans. It is a potent pathogen in a septic injury model of Drosophila melanogaster since a few bacteria directly injected in the body cavity kill the insect within a day. In contrast, flies do not succumb to ingested bacteria for days even though some bacteria cross the intestinal barrier into the hemolymph within hours. The mechanisms by which S. marcescens attacks enterocytes and damages the intestinal epithelium remain uncharacterized. To better understand intestinal infections, we performed a genetic screen for loss of virulence of ingested S. …

Understanding Information Needs And Barriers To Accessing Health Information Across All Stages Of Pregnancy: Systematic Review, Yu Lu, Laura A Barrett, Rebecca Z Lin, Muhammad Amith, Cui Tao, Zhe He

Open Access Publications

BACKGROUND: Understanding consumers' health information needs across all stages of the pregnancy trajectory is crucial to the development of mechanisms that allow them to retrieve high-quality, customized, and layperson-friendly health information.

OBJECTIVE: The objective of this study was to identify research gaps in pregnancy-related consumer information needs and available information from different sources.

METHODS: We conducted a systematic review of CINAHL, Cochrane, PubMed, and Web of Science for relevant articles that were published from 2009 to 2019. The quality of the included articles was assessed using the Critical Appraisal Skills Program. A descriptive data analysis was performed on these articles. …

Eml1 Is Essential For Retinal Photoreceptor Migration And Survival, Deepak Poria, Chi Sun, Andrea Santeford, Michel Kielar, Rajendra S Apte, Oleg G Kisselev, Shimming Chen, Vladimir J Kefalov

Open Access Publications

Calcium regulates the response sensitivity, kinetics and adaptation in photoreceptors. In striped bass cones, this calcium feedback includes direct modulation of the transduction cyclic nucleotide-gated (CNG) channels by the calcium-binding protein CNG-modulin. However, the possible role of EML1, the mammalian homolog of CNG-modulin, in modulating phototransduction in mammalian photoreceptors has not been examined. Here, we used mice expressing mutant Eml1 to investigate its role in the development and function of mouse photoreceptors using immunostaining, in-vivo and ex-vivo retinal recordings, and single-cell suction recordings. We found that the mutation of Eml1 causes significant changes in the mouse retinal structure characterized by …

Current And Future Approaches To Classify Vuss In Lgmd-Related Genes, Chengcheng Li, Gabe Haller, Conrad C Weihl

Open Access Publications

Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a major challenge in genetic test interpretation and disease diagnosis. Understanding the phenotypic consequences of VUSs can provide clinical guidance regarding LGMD risk and therapy. In this review, we provide a brief overview of the subtypes of LGMD, disease diagnosis, current classification systems for investigating VUSs, and a potential deep mutational scanning approach to classify VUSs in LGMD-related genes.

The Social Cerebellum: A Large-Scale Investigation Of Functional And Structural Specificity And Connectivity, Athanasia Metoki, Yin Wang, Ingrid R Olson

2020-Current year OA Pubs

The cerebellum has been traditionally disregarded in relation to nonmotor functions, but recent findings indicate it may be involved in language, affective processing, and social functions. Mentalizing, or Theory of Mind (ToM), is the ability to infer mental states of others and this skill relies on a distributed network of brain regions. Here, we leveraged large-scale multimodal neuroimaging data to elucidate the structural and functional role of the cerebellum in mentalizing. We used functional activations to determine whether the cerebellum has a domain-general or domain-specific functional role, and effective connectivity and probabilistic tractography to map the cerebello-cerebral mentalizing network. We …

Dietary Patterns Are Associated With Improved Ovarian Reserve In Overweight And Obese Women: A Cross-Sectional Study Of The Lifestyle And Ovarian Reserve (Lore) Cohort, Ashley M Eskew, Bronwyn S Bedrick, Jorge E Chavarro, Joan K Riley, Emily S Jungheim

2020-Current year OA Pubs

BACKGROUND: Growing evidence suggests that adherence to certain dietary patterns is associated with improved fecundity and reproductive outcomes in the general population and infertile couples assisted reproductive treatments. The objective of this study was to assess if dietary patterns are associated with ovarian reserve in reproductive age women without a history of infertility.

METHODS: This was a cross-sectional study of 185 women in the Lifestyle and Ovarian Reserve (LORe) cohort. Women aged 18-44 without a history of infertility were recruited from the local community at an academic medical center. Subjects completed validated food frequency and physical activity questionnaires to assess …

Release Of Chk-2 From Ppm-1.D Anchorage Schedules Meiotic Entry, Antoine Baudrimont, Dimitra Paouneskou, Ariz Mohammad, Raffael Lichtenberger, Joshua Blundon, Yumi Kim, Markus Hartl, Sebastian Falk, Tim Schedl, Verena Jantsch

Open Access Publications

Transition from the stem/progenitor cell fate to meiosis is mediated by several redundant posttranscriptional regulatory pathways in

Sustained Efficacy And Safety Of Burosumab, A Monoclonal Antibody To Fgf23, In Children With X-Linked Hypophosphatemia, Agnès Linglart, Erik A Imel, Michael P Whyte, Anthony A Portale, Wolfgang Högler, Annemieke M Boot, Raja Padidela, William Van't Hoff, Gary S Gottesman, Angel Chen, Alison Skrinar, Mary Scott Roberts, Thomas O Carpenter

2020-Current year OA Pubs

PURPOSE: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH.

METHODS: After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every …

Cardiac Outcomes Of Subjects On Adjuvant Trastuzumab Emtansine Vs Paclitaxel In Combination With Trastuzumab For Stage I Her2-Positive Breast Cancer (Atempt) Study (Tbcrc033): A Randomized Controlled Trial, Romualdo Barroso-Sousa, Ron Bose, Et Al

Open Access Publications

No abstract provided.

Cell Specific Peripheral Immune Responses Predict Survival In Critical Covid-19 Patients, Junedh M Amrute, Alexandra M Perry, Gautam Anand, Carlos Cruchaga, Karl G Hock, Christopher W Farnsworth, Gwendalyn J Randolph, Kory J Lavine, Ashley L Steed

Open Access Publications

SARS-CoV-2 triggers a complex systemic immune response in circulating blood mononuclear cells. The relationship between immune cell activation of the peripheral compartment and survival in critical COVID-19 remains to be established. Here we use single-cell RNA sequencing and Cellular Indexing of Transcriptomes and Epitomes by sequence mapping to elucidate cell type specific transcriptional signatures that associate with and predict survival in critical COVID-19. Patients who survive infection display activation of antibody processing, early activation response, and cell cycle regulation pathways most prominent within B-, T-, and NK-cell subsets. We further leverage cell specific differential gene expression and machine learning to …

A Diffusion Mri-Based Spatiotemporal Continuum Of The Embryonic Mouse Brain For Probing Gene-Neuroanatomy Connections, Dan Wu, Linda J Richards, Zhiyong Zhao, Zuozhen Cao, Wanrong Luo, Wei Shao, Song-Hai Shi, Michael I Miller, Susumu Mori, Seth Blackshaw, Jiangyang Zhang

Open Access Publications

The embryonic mouse brain undergoes drastic changes in establishing basic anatomical compartments and laying out major axonal connections of the developing brain. Correlating anatomical changes with gene-expression patterns is an essential step toward understanding the mechanisms regulating brain development. Traditionally, this is done in a cross-sectional manner, but the dynamic nature of development calls for probing gene-neuroanatomy interactions in a combined spatiotemporal domain. Here, we present a four-dimensional (4D) spatiotemporal continuum of the embryonic mouse brain from E10.5 to E15.5 reconstructed from diffusion magnetic resonance microscopy (dMRM) data. This study achieved unprecedented high-definition dMRM at 30- to 35-µm isotropic resolution, …

Therapeutic Efficacy Of 177lu-Labeled A20fmdv2 Peptides Targeting Ανβ6, Truc Thao Huynh, Sreeja Sreekumar, Cedric Mpoy, Buck Edward Rogers

2020-Current year OA Pubs

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