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Stub1 Suppresseses Tumorigenesis And Chemoresistance Through Antagonizing Yap1 Signaling, Dong-E Tang, Yong Dai, Lie-Wen Lin, Yong Xu, Dong-Zhou Liu, Xiao-Ping Hong, Hao-Wu Jiang, Song-Hui Xu

Open Access Publications

Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. …

Association Of Circulating Ceramides With Cardiac Structure And Function In The Community: The Framingham Heart Study, Chike C Nwabuo, Meredith Duncan, Vanessa Xanthakis, Linda R Peterson, Gary F Mitchell, David Mcmanus, Susan Cheng, Ramachandran S. Vasan

Open Access Publications

Background A higher circulating plasma ceramide ratio (C16:0/C24:0) is associated with an increased risk of heart failure, even after accounting for standard risk factors including lipid markers. However, the pathobiological mechanisms that underlie this association are incompletely understood. We tested the hypothesis that plasma ceramide ratio (C16:0/C24:0) is associated with adverse cardiac remodeling in the community. Methods and Results We evaluated 2652 Framingham Offspring Study participants (mean age, 66±9 years; 55% women) who attended their eighth examination cycle and underwent routine echocardiography and liquid chromatography-tandem mass spectrometry-based assays for circulating ceramide concentrations. We used multivariable linear regression models to relate …

Astrovirus Replication In Human Intestinal Enteroids Reveals Multi-Cellular Tropism And An Intricate Host Innate Immune Landscape, Abimbola O. Kolawole, Andrew B Janowski, David Wang, Christiane E. Wobus, Et Al.

Open Access Publications

Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLB-type and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE …

Transcriptional And Epigenetic Regulation Of Cardiac Electrophysiology, Jesus Jimenez, Stacey L Rentschler

Open Access Publications

Spatiotemporal gene expression during cardiac development is a highly regulated process. Activation of key signaling pathways involved in electrophysiological programming, such as Notch and Wnt signaling, occurs in early cardiovascular development and these pathways are reactivated during pathologic remodeling. Direct targets of these signaling pathways have also been associated with inherited arrhythmias such as Brugada syndrome and arrhythmogenic cardiomyopathy. In addition, evidence is emerging from animal models that reactivation of Notch and Wnt signaling during cardiac pathology may predispose to acquired arrhythmias, underscoring the importance of elucidating the transcriptional and epigenetic effects on cardiac gene regulation. Here, we highlight specific …

A Human Stat1 Gain-Of-Function Mutation Impairs Cd8 + T Cell Responses Against Gammaherpesvirus 68, Wei Qian, Cathrine A Miner, Harshad Ingle, Derek J Platt, Megan T Baldridge, Jonathan J Miner

Open Access Publications

Autosomal dominant STAT1 mutations in humans have been associated with chronic mucocutaneous candidiasis (CMC), as well as with increased susceptibility to herpesvirus infections. Prior studies have focused on mucosal and Th17-mediated immunity against

Casein Kinase 1 Family Proteins Promote Slimb-Dependent Expanded Degradation, Alexander D. Fulford, Maxine V. Holder, David Frith, Ambrosius P. Snijders, Nicolas Tapon, Paulo S. Ribeiro

Open Access Publications

Hippo signalling integrates diverse stimuli related to epithelial architecture to regulate tissue growth and cell fate decisions. The Hippo kinase cascade represses the growth-promoting transcription co-activator Yorkie. The FERM protein Expanded is one of the main upstream Hippo signalling regulators in

Feasibility Of Detecting Change In Backscattered Energy Of Acoustic Harmonics In Locally Heated Tissues, Borna Maraghechi, Michael C Kolios, Jahan Tavakkoli

Open Access Publications

No abstract provided.

Inhibition Of 4-Aminobutyrate Aminotransferase Protects Against Injury-Induced Osteoarthritis In Mice, Jie Shen, Cuicui Wang, Jun Ying, Taotao Xu, Audrey Mcalinden, Regis J. O'Keefe

Open Access Publications

Recently we demonstrated that ablation of the DNA methyltransferase enzyme, Dnmt3b, resulted in catabolism and progression of osteoarthritis (OA) in murine articular cartilage through a mechanism involving increased mitochondrial respiration. In this study, we identify 4-aminobutyrate aminotransferase (Abat) as a downstream target of Dnmt3b. Abat is an enzyme that metabolizes γ-aminobutyric acid to succinate, a key intermediate in the tricarboxylic acid cycle. We show that Dnmt3b binds to the Abat promoter, increases methylation of a conserved CpG sequence just upstream of the transcriptional start site, and inhibits Abat expression. Dnmt3b deletion in articular chondrocytes results in reduced methylation of the …

Virus-Induced Cochlear Inflammation In Newborn Mice Alters Auditory Function, Cathy Yea Won Sung, Maria C. Seleme, Shelby Payne, Stipan Jonjic, Keiko Hirose, William Britt

Open Access Publications

Although human cytomegalovirus (HCMV) is a known cause of sensorineural hearing loss in infants with congenital HCMV (cCMV) infections, mechanisms that contribute to sensorineural hearing loss (SNHL) in infants with cCMV infection are not well defined. Using a murine model of CMV infection during auditory development, we have shown that peripheral infection of newborn mice with murine CMV (MCMV) results in focal infection of the cochlea and virus-induced cochlear inflammation. Approximately 50%-60% of infected mice exhibited increased auditory brainstem response (ABR) thresholds across a range of sound frequencies. Histological analyses of the cochlea in MCMV-infected mice with elevated ABR thresholds …

Vincristine And Bortezomib Use Distinct Upstream Mechanisms To Activate A Common Sarm1-Dependent Axon Degeneration Program, Stefanie Geisler, Ryan A Doan, Galen C Cheng, Aysel Cetinkaya-Fisgin, Shay X Huang, Ahmet Höke, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge …

Association Of Timing Of Adverse Childhood Experiences And Caregiver Support With Regionally Specific Brain Development In Adolescents, Joan L. Luby, Rebecca Tillman, Deanna M. Barch

Open Access Publications

Importance: Few data are available to inform the associations and timing of the associations between adversity, caregiver support, and brain outcomes. Consideration of timing has important public health implications to inform more precise prevention strategies.

Objective: To evaluate the timing and regional specificity of the association between adverse childhood experiences (ACEs) and caregiver support to structural development of limbic and striatal brain regions in middle childhood and adolescence.

Design, Setting, and Participants: This 15-year developmental, neuroimaging cohort study included 211 children and their caregivers screened from day care centers and preschools in the St Louis, Missouri, metropolitan area during the …

Videofluoroscopic Swallow Study Features Of Lower Esophageal Sphincter Achalasia-Like Syndrome In Dogs, Megan E Grobman, James Schachtel, C Prakash Gyawali, Teresa E Lever, Carol R Reinero

Open Access Publications

BACKGROUND: Megaesophagus (ME) carries a poor long-term prognosis in dogs. In people, lower esophageal sphincter (LES) disorders causing functional obstruction are rare causes of ME that may respond to targeted treatment. Functional LES disorders are reported rarely in dogs because of challenges in diagnostic methodologies.

HYPOTHESIS/OBJECTIVES: To identify dogs with videofluoroscopic swallow study (VFSS) features of LES achalasia-like syndrome (LES-AS). We hypothesized that dogs with LES-AS could be distinguished from normal dogs using standardized VFSS criteria.

ANIMALS: Dogs with LES-AS by VFSS (n = 19), healthy normal dogs (n = 20).

METHODS: Retrospective study. One-hundred thirty dogs presented to the …

An Open-Source, Automated Home-Cage Sipper Device For Monitoring Liquid Ingestive Behavior In Rodents, Elizabeth Godynyuk, Maya N Bluitt, Jessica R Tooley, Alexxai V Kravitz, Meaghan C Creed

Open Access Publications

Measuring ingestive behavior of liquids in rodents is commonly used in studies of reward, metabolism, and circadian biology. Common approaches for measuring liquid intake in real time include computer-tethered lickometers or video-based systems. Additionally, liquids can be measured or weighed to determine the amount consumed without real-time sensing. Here, we built a photobeam-based sipper device that has the following advantages over traditional methods: (1) it is battery powered and fits in vivarium caging to allow home-cage measurements; (2) it quantifies the intake of two different liquids simultaneously for preference studies; (3) it is low cost and easily constructed, enabling high-throughput …

Tyk2 Promotes Malignant Peripheral Nerve Sheath Tumor Progression Through Inhibition Of Cell Death, Wenjing Qin, Abigail Godec, Xiaochun Zhang, Cuige Zhu, Jieya Shao, Yu Tao, Xianzhang Bu, Angela C Hirbe

Open Access Publications

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise most commonly in the setting of the Neurofibromatosis Type 1 (NF1) cancer predisposition syndrome. Despite aggressive multimodality therapy, outcomes are dismal and most patients die within 5 years of diagnosis. Prior genomic studies in our laboratory identified tyrosine kinase 2 (TYK2) as a frequently mutated gene in MPNST. Herein, we explored the function of TYK2 in MPNST pathogenesis.

METHODS: Immunohistochemistry was utilized to examine expression of TYK2 in MPNSTs and other sarcomas. To establish a role for TYK2 in MPNST pathogenesis, murine and human TYK2 knockdown and knockout …

Steady-State Activation And Modulation Of The Synaptic-Type Α1Β2Γ2l Gabaa Receptor By Combinations Of Physiological And Clinical Ligands, Allison L Germann, Spencer R Pierce, Thomas C Senneff, Ariel B Burbridge, Joe Henry Steinbach, Gustav Akk

Open Access Publications

The synaptic α1β2γ2 GABA

Dhx33 Interacts With Ap-2Β To Regulate Bcl-2 Gene Expression And Promote Cancer Cell Survival, Jiuling Wang, Weimin Feng, Zhen Yuan, Jason D. Weber, Yandong Zhang

Open Access Publications

The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of

Omnipresence Of Inflammasome Activities In Inflammatory Bone Diseases, Yael Alippe, Gabriel Mbalaviele

Open Access Publications

The inflammasomes are intracellular protein complexes that are assembled in response to a variety of perturbations including infections and injuries. Failure of the inflammasomes to rapidly clear the insults or restore tissue homeostasis can result in chronic inflammation. Recurring inflammation is also provoked by mutations that cause the constitutive assembly of the components of these protein platforms. Evidence suggests that chronic inflammation is a shared mechanism in bone loss associated with aging, dysregulated metabolism, autoinflammatory, and autoimmune diseases. Mechanistically, inflammatory mediators promote bone resorption while suppressing bone formation, an imbalance which over time leads to bone loss and increased fracture …

Four-Jointed Knock-Out Delays Renal Failure In An Adpkd Model With Kidney Injury, Chiara Formica, Hester Happé, Kimberley Am Veraar, Andrea Vortkamp, Marion Scharpfenecker, Helen Mcneill, Dorien Jm Peters

Open Access Publications

Autosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid-filled cysts in the kidneys which lead to end-stage renal disease (ESRD). In the majority of cases, the disease is caused by a mutation in the Pkd1 gene. In a previous study, we demonstrated that renal injury can accelerate cyst formation in Pkd1 knock-out (KO) mice. In that study, we found that after injury four-jointed (Fjx1), an upstream regulator of planar cell polarity and the Hippo pathway, was aberrantly expressed in Pkd1 KO mice compared to WT. Therefore, we hypothesised a role for Fjx1 in injury/repair and cyst formation. …

Comparative Genomics Of Antibiotic-Resistant Uropathogens Implicates Three Routes For Recurrence Of Urinary Tract Infections, Robert Thänert, Kimberly A Reske, Tiffany Hink, Meghan A Wallace, Bin Wang, Drew J Schwartz, Sondra Seiler, Candice Cass, Carey-Ann D. Burnham, Erik R Dubberke, Jennie H Kwon, Gautam Dantas

Open Access Publications

The rise of antimicrobial resistance in uropathogens has complicated the management of urinary tract infections (UTIs), particularly in patients who are afflicted by recurrent episodes of UTIs. Antimicrobial-resistant (AR) uropathogens persistently colonizing individuals at asymptomatic time points have been implicated in the pathophysiology of UTIs. The dynamics of uropathogen persistence following the resolution of symptomatic disease are, however, mostly unclear. To further our understanding, we determined longitudinal AR uropathogen carriage and clonal persistence of uropathogenic

Sensorimotor Coding Of Vermal Granule Neurons In The Developing Mammalian Cerebellum, Kelly H. Markwalter, Yue Yang, Timothy E. Holy, Azad Bonni

Open Access Publications

The vermal cerebellum is a hub of sensorimotor integration critical for postural control and locomotion, but the nature and developmental organization of afferent information to this region have remained poorly understood

Mucosal Infection Rewires Tnfɑ Signaling Dynamics To Skew Susceptibility To Recurrence, Lu Yu, Valerie P. O'Brien, Jonathan Livny, Denise Dorsey, Nirmalya Bandyopadhyay, Marco Colonna, Michael G. Caparon, Elisha D.O. Roberson, Scott J. Hultgren, Thomas Hannan

Open Access Publications

A mucosal infectious disease episode can render the host either more or less susceptible to recurrent infection, but the specific mechanisms that tip the balance remain unclear. We investigated this question in a mouse model of recurrent urinary tract infection and found that a prior bladder infection resulted in an earlier onset of tumor necrosis factor-alpha (TNFɑ)-mediated bladder inflammation upon subsequent bacterial challenge, relative to age-matched naive mice. However, the duration of TNFɑ signaling activation differed according to whether the first infection was chronic (Sensitized) or self-limiting (Resolved). TNFɑ depletion studies revealed that transient early-phase TNFɑ signaling in Resolved mice …

Toxoplasma Gondii Infection Drives Conversion Of Nk Cells Into Ilc1-Like Cells, Eugene Park, Swapneel Patel, Qiuling Wang, Prabhakar Andhey, Konstantin Zaitsev, Sophia Porter, Maxwell Hershey, Michael Bern, Beatrice Plougastel-Douglas, Patrick Collins, Marco Colonna, Kenneth M. Murphy, Eugene Oltz, Maxim Artyomov, L David Sibley, Wayne M. Yokoyama

Open Access Publications

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here, we describe

Pneumothorax Following Combination Chemotherapy With Bevacizumab: A Case Report And Review Of The Literature, Taha Alrifai, Raya Saba, Dana Rifai, Sarbagya Pandit, Kelley E Kozma

Open Access Publications

Bevacizumab (BV) is a humanized monoclonal antibody that inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF). The addition of BV to combination chemotherapy has been shown to improve the outcomes in several malignancies, including colorectal carcinoma (CRC). However, the use of BV has been associated with adverse effects, including hypertension, hemorrhage, proteinuria, delayed wound healing and bowel perforation. Pneumothorax (PTX) as an adverse event associated with BV use has rarely been reported. We herein report the case of a 68-year-old female patient with a history of metastatic CRC treated with combination chemotherapy, including BV, who presented with complaints of …

Circulating Serum Fatty Acid Synthase Is Elevated In Patients With Diabetes And Carotid Artery Stenosis And Is Ldl-Associated, Gayan S De Silva, Kshitij Desai, Malik Darwech, Uzma Naim, Xiaohua Jin, Sangeeta Adak, Nikolai Harroun, Luis A Sanchez, Clay F Semenkovich, Mohamed A Zayed

Open Access Publications

BACKGROUND AND AIMS: Diabetes is an independent risk factor for carotid artery stenosis (CAS). Fatty acid synthase (FAS), an essential de novo lipogenesis enzyme, has increased activity in the setting of diabetes that leads to altered lipid metabolism. Circulating FAS (cFAS) was recently observed in the blood of patients with hyperinsulinemia and cancer. We thought to evaluate the origin of cFAS and its role in diabetes-associated CAS.

METHODS: Patients with diabetes and no diabetes, undergoing carotid endarterectomy (CEA) for CAS, were prospectively enrolled for collection of plaque and fasting serum. FPLC was used to purify lipoprotein fractions, and ELISA was …

Quantification Of Image Texture In X-Ray Phase-Contrast-Enhanced Projection Images Of In Vivo Mouse Lungs Observed At Varied Inflation Pressures, Frank J Brooks, Sean P Gunsten, Sunil K Vasireddi, Steven L Brody, Mark A Anastasio

Open Access Publications

To date, there are very limited noninvasive, regional assays of in vivo lung microstructure near the alveolar level. It has been suggested that x-ray phase-contrast enhanced imaging reveals information about the air volume of the lung; however, the image texture information in these images remains underutilized. Projection images of in vivo mouse lungs were acquired via a tabletop, propagation-based, X-ray phase-contrast imaging system. Anesthetized mice were mechanically ventilated in an upright position. Consistent with previously published studies, a distinct image texture was observed uniquely within lung regions. Lung regions were automatically identified using supervised machine learning applied to summary measures …

Novel Cell Adhesion/Migration Pathways Are Predictive Markers Of Hdac Inhibitor Resistance In Cutaneous T Cell Lymphoma, Jared M Andrews, Jennifer A Schmidt, Kenneth R Carson, Amy C Musiek, Neha Mehta-Shah, Jacqueline E Payton

Open Access Publications

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy.

METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks …

Host And Viral Mechanisms Of Congenital Zika Syndrome, Brooke Liang, José Paulo Guida, Maria Laura Costa Do Nascimento, Indira U Mysorekar

Open Access Publications

In 2015-2016, in the Americas, and especially in northeast Brazil, a significant number of cases of microcephaly and other congenital brain abnormalities were linked with an outbreak of Zika virus (ZIKV) infection in pregnant women. While maternal symptoms of ZIKV are generally mild and self-limiting, clinical presentation in fetuses and newborns infected is extensive and includes microcephaly, decreased cortical development, atrophy and hypoplasia of the cerebellum and cerebellar vermis, arthrogryposis, and polyhydramnios. The term congenital ZIKV syndrome (CZS) was introduced to describe the range of findings associated with maternal-fetal ZIKV transmission. ZIKV is primarily transmitted by

Precision Delivery Of Ras-Inhibiting Sirna To Kras Driven Cancer Via Peptide-Based Nanoparticles, Matthew S. Strand, Bradley A. Krasnick, Hua Pan, Xiuli Zhang, Ye Bi, Candace Brooks, Christopher Wetzel, Narendra Sankpal, Timothy Fleming, S Peter Goedegebuure, David G. Denardo, William E. Gillanders, William G. Hawkins, Samuel A. Wickline, Ryan C. Fields

Open Access Publications

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient …

Spinal V2b Neurons Reveal A Role For Ipsilateral Inhibition In Speed Control, Rebecca A. Callahan, Richard Roberts, Mohini Sengupta, Yukiko Kimura, Shin-Ichi Higashijima, Martha W. Bagnall

Open Access Publications

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These V2b subclasses synapse directly onto motor neurons with differential targeting …

Situating Dissemination And Implementation Sciences Within And Across The Translational Research Spectrum, Aaron L Leppin, Jane E Mahoney, Kathleen R Stevens, Stephen J Bartels, Laura-Mae Baldwin, Rowena J Dolor, Enola K Proctor, Linda Scholl, Justin B Moore, Ana A Baumann, Catherine L Rohweder, Joan Luby, Paul Meissner

Open Access Publications

The efficient and effective movement of research into practice is acknowledged as crucial to improving population health and assuring return on investment in healthcare research. The National Center for Advancing Translational Science which sponsors Clinical and Translational Science Awards (CTSA) recognizes that dissemination and implementation (D&I) sciences have matured over the last 15 years and are central to its goals to shift academic health institutions to better align with this reality. In 2016, the CTSA Collaboration and Engagement Domain Task Force chartered a D&I Science Workgroup to explore the role of D&I sciences across the translational research spectrum. This special …