Digital Commons Network^™

Advances And Gaps In Sars-Cov-2 Infection Models, César Muñoz-Fontela, Michael S. Diamond, Et Al

Open Access Publications

The global response to Coronavirus Disease 2019 (COVID-19) is now facing new challenges such as vaccine inequity and the emergence of SARS-CoV-2 variants of concern (VOCs). Preclinical models of disease, in particular animal models, are essential to investigate VOC pathogenesis, vaccine correlates of protection and postexposure therapies. Here, we provide an update from the World Health Organization (WHO) COVID-19 modeling expert group (WHO-COM) assembled by WHO, regarding advances in preclinical models. In particular, we discuss how animal model research is playing a key role to evaluate VOC virulence, transmission and immune escape, and how animal models are being refined to …

Disruption Of Thymic Central Tolerance By Infection With Murine Roseolovirus Induces Autoimmune Gastritis, Tarin M. Bigley, Liping Yang, Liang-I Kang, Jose B. Saenz, Francisco Victorino, Wayne M. Yokoyama

Open Access Publications

Infections with herpesviruses, including human roseoloviruses, have been proposed to cause autoimmune disease, but defining a causal relationship and mechanism has been difficult due to the ubiquitous nature of infection and development of autoimmunity long after acute infection. Murine roseolovirus (MRV) is highly related to human roseoloviruses. Herein we show that neonatal MRV infection induced autoimmune gastritis (AIG) in adult mice in the absence of ongoing infection. MRV-induced AIG was dependent on replication during the neonatal period and was CD4+ T cell and IL-17 dependent. Moreover, neonatal MRV infection was associated with development of a wide array of autoantibodies in …

Sonobiopsy For Minimally Invasive, Spatiotemporally-Controlled, And Sensitive Detection Of Glioblastoma-Derived Circulating Tumor Dna, Christopher Pacia, Jinyun Yuan, Yimei Yue, Lu Xu, Arash Nazeri, Rupen Desai, H. Michael Gach, Xiaowei Wang, Michael Talcott, Aadel Chaudhuri, Gavin Dunn, Eric Leuthardt, Hong Chen

Open Access Publications

No abstract provided.

Sarm1 Activation Produces Cadpr To Increase Intra-Axonal Ca++ And Promote Axon Degeneration In Pipn, Yihang Li, Maria F. Pazyra-Murphy, Daina Avizonis, Mariana De Sá Tavares Russo, Sophia Tang, Chiung-Ya Chen, Yi-Ping Hsueh, Johann S. Bergholz, Tao Jiang, Jean J. Zhao, Jian Zhu, Kwang Woo Ko, Jeffrey Milbrandt, Aaron Diantonio, Rosalind A. Segal

Open Access Publications

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or …

The 2021 Faseb Science Research Conference On Nad Metabolism And Signaling, Vera Gorbunova, Shin-Ichiro Imai, Et Al

Open Access Publications

No abstract provided.

Epigenetic Regulation Of Human T‐Cell Leukemia Virus Gene Expression, Lee Ratner

Open Access Publications

No abstract provided.

Dopamine D4 Receptor Is A Regulator Of Morphine-Induced Plasticity In The Rat Dorsal Striatum, Alicia Rivera, Diana Suarez-Boomgard, Cristina Miguelez, Alejandra Valderrama-Carvajal, Jerome Baufreton, Kirill Shumilov, Anne Taupignon, Belen Gago, M.Angeles Real

Open Access Publications

No abstract provided.

Transition From Cmyc To L-Myc During Dendritic Cell Development Coordinated By Rising Levels Of Irf8, David A. Anderson, Feiya Ou, Sunkyung Kim, Theresa L. Murphy, Kenneth M. Murphy

Open Access Publications

During dendritic cell (DC) development, Myc expression in progenitors is replaced by Mycl in mature DCs, but when and how this transition occurs is unknown. We evaluated DC development using reporters for MYC, MYCL, and cell cycle proteins Geminin and CDT1 in wild-type and various mutant mice. For classical type 1 dendritic cells (cDC1s) and plasmacytoid DCs (pDCs), the transition occurred upon their initial specification from common dendritic cell progenitors (CDPs) or common lymphoid progenitors (CLPs), respectively. This transition required high levels of IRF8 and interaction with PU.1, suggesting the use of EICEs within Mycl enhancers. In pDCs, maximal MYCL …

M6a Modifications Regulate Intestinal Immunity And Rotavirus Infection, Anmin Wang, Gaopeng Hou, Siyuan Ding, Et Al

Open Access Publications

N6-methyladenosine (m6A) is an abundant mRNA modification and affects many biological processes. However, how m6A levels are regulated during physiological or pathological processes such as virus infections, and the in vivo function of m6A in the intestinal immune defense against virus infections are largely unknown. Here, we uncover a novel antiviral function of m6A modification during rotavirus (RV) infection in small bowel intestinal epithelial cells (IECs). We found that rotavirus infection induced global m6A modifications on mRNA transcripts by down-regulating the m6a eraser ALKBH5. Mice lacking the m6A writer enzymes METTL3 in IECs (

A Test Of The Pioneer Factor Hypothesis Using Ectopic Liver Gene Activation, Jeffrey L. Hansen, Kaiser J. Loell, Barak A. Cohen

Open Access Publications

The pioneer factor hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (non-PFs) that activate batteries of silent genes. The PFH predicts that ectopic gene activation requires the sequential activity of qualitatively different TFs. We tested the PFH by expressing the endodermal PF FOXA1 and non-PF HNF4A in K562 lymphoblast cells. While co-expression of FOXA1 and HNF4A activated a burst of endoderm-specific gene expression, we found no evidence for a functional distinction between these two TFs. When expressed independently, both TFs bound and …

The Mutationathon Highlights The Importance Of Reaching Standardization In Estimates Of Pedigree-Based Germline Mutation Rates, Lucie A. Bergeron, Tychele Turner, Et Al

Open Access Publications

In the past decade, several studies have estimated the human per-generation germline mutation rate using large pedigrees. More recently, estimates for various nonhuman species have been published. However, methodological differences among studies in detecting germline mutations and estimating mutation rates make direct comparisons difficult. Here, we describe the many different steps involved in estimating pedigree-based mutation rates, including sampling, sequencing, mapping, variant calling, filtering, and appropriately accounting for false-positive and false-negative rates. For each step, we review the different methods and parameter choices that have been used in the recent literature. Additionally, we present the results from a 'Mutationathon,' a …

Intrinsic Mechanisms In The Gating Of Resurgent Na+ Currents, Joseph L. Ransdell, Jonathan D. Moreno, Druv Bhagavan, Jonathan R. Silva, Jeanne M. Nerbonne

Open Access Publications

The resurgent component of the voltage-gated sodium current (I

Tumor Lysis Syndrome In A Patient With Metastatic Endometrial Cancer Treated With Lattice Stereotactic Body Radiation Therapy, Joshua P Schiff, Matthew B Spraker, Sai Duriseti, Sana Shaikh, Haris F Murad, David G Mutch, Clifford G Robinson, James Kavanaugh, Alexander J Lin

Open Access Publications

No abstract provided.

Loss Of Kmt2c Reprograms The Epigenomic Landscape In Hpscs Resulting In Nodal Overexpression And A Failure Of Hemogenic Endothelium Specification, Shailendra Maurya, Wei Yang, Minori Tamai, Qiang Zhang, Petra Erdmann-Gilmore, Amelia Bystry, Fernanda Martins Rodrigues, Mark C Valentine, Wing H Wong, Reid Townsend, Todd E Druley

Open Access Publications

Germline or somatic variation in the family of KMT2 lysine methyltransferases have been associated with a variety of congenital disorders and cancers. Notably,

Augmented Cardiac Growth Hormone Signaling Contributes To Cardiomyopathy Following Genetic Disruption Of The Cardiomyocyte Circadian Clock, Ravi Sonkar, Ryan Berry, Mary N Latimer, Sumanth D Prabhu, Martin E Young, Stuart J Frank

Open Access Publications

Circadian clocks regulate numerous biological processes, at whole body, organ, and cellular levels. This includes both hormone secretion and target tissue sensitivity. Although growth hormone (GH) secretion is time-of-day-dependent (increased pulse amplitude during the sleep period), little is known regarding whether circadian clocks modulate GH sensitivity in target tissues. GH acts in part through induction of insulin-like growth factor 1 (IGF1), and excess GH/IGF1 signaling has been linked to pathologies such as insulin resistance, acromegaly, and cardiomyopathy. Interestingly, genetic disruption of the cardiomyocyte circadian clock leads to cardiac adverse remodeling, contractile dysfunction, and reduced lifespan. These observations led to the …

Steroid Hormone Signaling Activates Thermal Nociception During Drosophila Peripheral Nervous System Development, Jacob S. Jaszczak, Laura Devault, Lily Yeh Jan, Yuh Nung Jan

Open Access Publications

Sensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in development.

Fracture Healing Is Delayed In The Absence Of Gasdermin-Interleukin-1 Signaling, Kai Sun, Chun Wang, Jianqiu Xiao, Michael D. Brodt, Luorongxin Yuan, Tong Yang, Yael Alippe, Huimin Hu, Dingjun Hao, Yousef Abu-Amer, Matthew J. Silva, Jie Shen, Gabriel Mbalaviele

Open Access Publications

Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking …

Tourette Syndrome Research Highlights From 2020, Andreas Hartmann, Cyril Atkinson-Clement, Christel Depienne, Kevin Black

Open Access Publications

We present here research from 2020 relevant to Tourette syndrome (TS). The authors briefly summarize a few reports they consider most important or interesting.

Sglt2 Inhibitors Therapy Protects Glucotoxicity-Induced Β-Cell Failure In A Mouse Model Of Human Katp-Induced Diabetes Through Mitigation Of Oxidative And Er Stress, Zeenat A. Shyr, Zihan Yan, Alessandro Ustione, Erin M. Egan, Maria S. Remedi

Open Access Publications

Progressive loss of pancreatic β-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and β-cell exhaustion. However, loss of β-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional β-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased …

Expert Guidance On Prophylaxis And Treatment Of Dermatologic Adverse Events With Tumor Treating Fields (Ttfields) Therapy In The Thoracic Region, Milan J Anadkat, Mario Lacouture, Adam Friedman, Zachary D Horne, Jae Jung, Benjamin Kaffenberger, Sujith Kalmadi, Liza Ovington, Rupesh Kotecha, Huda Ismail Abdullah, Federica Grosso

2020-Current year OA Pubs

Tumor Treating Fields (TTFields) are electric fields, delivered via wearable arrays placed on or near the tumor site, that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. As a first-in-class treatment, TTFields therapy is approved for use in newly diagnosed glioblastoma, recurrent glioblastoma, and pleural mesothelioma. Additionally, TTFields therapy is being investigated in non-small cell lung cancer (NSCLC), brain metastases from NSCLC, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and gastric adenocarcinoma. Because TTFields therapy is well tolerated and delivery is locoregional, there is low risk of additive systemic adverse events (AEs) when used …

Reciprocal Regulation Of Mitofusin 2-Mediated Mitophagy And Mitochondrial Fusion By Different Pink1 Phosphorylation Events, Jiajia Li, Xiawei Dang, Antonietta Franco, Gerald W Dorn

2020-Current year OA Pubs

Mitochondrial repair is essential to metabolic homeostasis. Outer mitochondrial membrane mitofusin (MFN) proteins orchestrate mitochondrial fusion that opposes mitochondrial degeneration caused by senescence. Depending upon physiological context, MFN2 can either mediate mitochondrial fusion or recruit cytosolic Parkin to initiate mitophagic elimination. Because it is not clear how these events are counter-regulated we engineered and expressed MFN2 mutants that mimic phosphorylated or non-phosphorylatable MFN2 at its PINK1 phosphorylation sites: T111, S378, and S442. By interrogating mitochondrial fusion, polarization status, and Parkin binding/mitophagy as a function of inferred MFN2 phosphorylation, we discovered that individual MFN2 phosphorylation events act as a biological "bar-code", …

White Matter Abnormalities In The Hdc Knockout Mouse, A Model Of Tic And Ocd Pathophysiology, Kantiya Jindachomthong, Chengran Yang, Yuegao Huang, Daniel Coman, Maximiliano Rapanelli, Fahmeed Hyder, Joseph Dougherty, Luciana Frick, Christopher Pittenger

2020-Current year OA Pubs

INTRODUCTION: An inactivating mutation in the

MATERIALS AND METHODS: We performed exploratory RNA-seq to identify pathological alterations in several brain regions in

RESULTS: Exploratory RNA-Seq analysis revealed, unexpectedly, that genes associated with oligodendrocytes and with myelin production are upregulated in the dorsal striatum of these mice. This was confirmed by qPCR, immunostaining, and immunoblotting. These results suggest an abnormality in myelination in the striatum. To test this in an intact mouse brain, we performed whole-brain

DISCUSSION: While the DTI literature in individuals with TS is sparse, these results are consistent with findings of disrupted descending cortical projections in patients with …

Primates Chunk Simultaneously-Presented Memoranda, Charles D Holmes, Shinung Ching, Lawrence H Snyder

2020-Current year OA Pubs

Though much research has characterized both the behavior and electrophysiology of spatial memory for single targets in non-human primates, we know much less about how multiple memoranda are handled. Multiple memoranda may interact in the brain, affecting the underlying representations. Mnemonic resources are famously limited, so items may compete for "space" in memory or may be encoded cooperatively or in a combined fashion. Understanding the mode of interaction will inform future neural studies. As a first step, we quantified interactions during a multi-item spatial memory task. Two monkeys were shown 1-4 target locations. After a delay, the targets reappeared with …

Influenza: Toward Understanding The Immune Response In The Young, Sonia Sakleshpur, Ashley L Steed

2020-Current year OA Pubs

Annually influenza causes a global epidemic resulting in 290,000 to 650,000 deaths and extracts a massive toll on healthcare and the economy. Infants and children are more susceptible to infection and have more severe symptoms than adults likely mitigated by differences in their innate and adaptive immune responses. While it is unclear the exact mechanisms with which the young combat influenza, it is increasingly understood that their immune responses differ from adults. Specifically, underproduction of IFN-γ and IL-12 by the innate immune system likely hampers viral clearance while upregulation of IL-6 may create excessive damaging inflammation. The infant's adaptive immune …

Analysis Of Neuronal Injury Transcriptional Response Identifies Ctcf And Yy1 As Co-Operating Factors Regulating Axon Regeneration, Oshri Avraham, Jimmy Le, Kathleen Leahy, Tiandao Li, Guoyan Zhao, Valeria Cavalli

2020-Current year OA Pubs

Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neurons

A Role For An Htlv-1 Vaccine?, Lee Ratner

2020-Current year OA Pubs

HTLV-1 is a global infection with 5-20 million infected individuals. Although only a minority of infected individuals develop myelopathy, lymphoproliferative malignancy, or inflammatory disorders, infection is associated with immunosuppression and shorter survival. Transmission of HTLV-1 is through contaminated blood or needles, mother-to-child exposure through breast-feeding, and sexual intercourse. HTLV-1 is a delta retrovirus that expresses immunogenic Gag, Envelope, TAX, and Hbz proteins. Neutralizing antibodies have been identified directed against the surface envelope protein, and cytotoxic T-cell epitopes within TAX have been characterized. Thus far, there have been few investigations of vaccines directed against each of these proteins, with limited responses, …

In And Out: Leishmania Metastasis By Hijacking Lymphatic System And Migrating Immune Cells, Baijayanti Jha, Marta Reverte, Catherine Ronet, Florence Prevel, Florence D Morgenthaler, Chantal Desponds, Lon-Fye Lye, Katherine L Owens, Leonardo Scarpellino, Lalit Kumar Dubey, Amélie Sabine, Tatiana V Petrova, Sanjiv A Luther, Stephen M Beverley, Nicolas Fasel

2020-Current year OA Pubs

The lymphatic system plays a crucial role in mounting immune response against intracellular pathogens, and recent studies have documented its role in facilitating tumor dissemination linked largely with cancer cells. However, in mucocutaneous leishmaniasis (MCL) caused by

Cd4+ T-Lymphocytes Exhibit Biphasic Kinetics Post-Myocardial Infarction, Vinay Kumar, Sumanth D Prabhu, Shyam S Bansal

2020-Current year OA Pubs

CD4

Cognitive And Brain Reserve Predict Decline In Adverse Driving Behaviors Among Cognitively Normal Older Adults, Samantha A Murphy, Ling Chen, Jason M Doherty, Prerana Acharyya, Noah Riley, Ann M Johnson, Alexis Walker, Hailee Domash, Maren Jorgensen, Sayeh Bayat, David B Carr, Beau M Ances, Ganesh M Babulal

2020-Current year OA Pubs

Daily driving is a multi-faceted, real-world, behavioral measure of cognitive functioning requiring multiple cognitive domains working synergistically to complete this instrumental activity of daily living. As the global population of older adult continues to grow, motor vehicle crashes become more frequent among this demographic. Cognitive reserve (CR) is the brain's adaptability or functional robustness despite damage, while brain reserve (BR) refers the structural, neuroanatomical resources. This study examined whether CR and BR predicted changes in adverse driving behaviors in cognitively normal older adults. Cognitively normal older adults (Clinical Dementia Rating 0) were enrolled from longitudinal studies at the Knight Alzheimer's …

Toward A Fully Implantable Ecosystem For Adaptive Neuromodulation In Humans: Preliminary Experience With The Cortec Braininterchange Device In A Canine Model, Gerwin Schalk, Samuel Worrell, Filip Mivalt, Alexander Belsten, Inyong Kim, Jonathan M Morris, Dora Hermes, Bryan T Klassen, Nathan P Staff, Steven Messina, Timothy Kaufmann, Jörn Rickert, Peter Brunner, Gregory A Worrell, Kai J Miller

2020-Current year OA Pubs

This article describes initial work toward an ecosystem for adaptive neuromodulation in humans by documenting the experience of implanting CorTec's BrainInterchange (BIC) device in a beagle canine and using the BCI2000 environment to interact with the BIC device. It begins with laying out the substantial opportunity presented by a useful, easy-to-use, and widely available hardware/software ecosystem in the current landscape of the field of adaptive neuromodulation, and then describes experience with implantation, software integration, and post-surgical validation of recording of brain signals and implant parameters. Initial experience suggests that the hardware capabilities of the BIC device are fully supported by …