Digital Commons Network^™

Cgas-Agonistic Spherical Nucleic Acids Reprogram The Glioblastoma Immune Microenvironment And Promote Antitumor Immunity, Akanksha S Mahajan, Corey Dussold, Seunghyun Kim, Rachel Jarvis, Lisa A Hurley, Serena Tommasini-Ghelfi, Jungsoo Park, Connor M Forsyth, Bin Zhang, Jason Miska, Amy B Heimberger, Chad A Mirkin, Alexander H Stegh

2020-Current year OA Pubs

The cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is an important DNA-sensing mechanism that increases T cell trafficking and activation in tumors and reverses the immunosuppressive phenotype of myeloid cells. Therefore, direct STING targeting using synthetic cyclic dinucleotides (CDNs) is an attractive strategy for treating lymphocyte-depleted and myeloid cell-enriched tumors, such as glioblastoma (GBM). However, inadequate bioavailability and poor cellular accumulation limit the clinical development of CDNs, particularly for noninvasive administration strategies. Spherical nucleic acids (SNAs) have emerged as promising modular constructs for creating therapeutic lead compounds for many diseases, including different forms of cancer. Here, we report the …

Lrp8 Is An Entry Receptor For Tick-Borne Encephalitis Viruses, Pengfei Li, Sean Hui, Zhenlu Chong, Michael N Nguyen, Stefanie P Muraro, Hana Janova, Hongming Ma, Shiqi Cao, Tomasz Kaszuba, Brian Imbiakha, Sathvik Palakurty, David A Price, Gaya K Amarasinghe, Daisy W Leung, Daved H Fremont, Michael S Diamond, Et Al.

2020-Current year OA Pubs

Orthoflaviviruses are a genus of arthropod-transmitted RNA viruses that infect humans and other vertebrate animals on a global scale, resulting in extensive morbidity and mortality. Among the orthoflaviviruses, tick-borne encephalitis viruses (TBEV) are an antigenic group that causes severe neurological disease in humans. However, the entry receptors for TBEV, which contribute to cell and tissue tropism, remain largely unknown. Because recent studies identified members of the low-density lipoprotein receptor (LDLR) family as possible receptors for some orthoflaviviruses and distantly related alphaviruses, we performed a targeted screen in transgenic cells expressing different LDLR members and identified LRP8 (also called ApoER2) as …

A Functional Clock In Only Two Dorsal Clock Neurons Is Sufficient To Restore The Basal Circadian Activity Pattern Of Drosophila Melanogaster, Nils Reinhard, Enrico Bertolini, Takuya Kuwahara, Manabu Sekiguchi, Dirk Rieger, Weihua Li, Paul H Taghert, Taishi Yoshii, Charlotte Helfrich-Förster

2020-Current year OA Pubs

Circadian clocks form complex networks to orchestrate the behavior and physiology of animals. Elucidating the organization of these clock networks is critical to understanding how circadian clocks achieve robust timing. Clock neurons have been best characterized in the model organism

Muscle Fatigue Arising Intrinsically From Sur2- But Not Kir6.1-Dependent Gain-Of-Function In Cantu Syndrome Mice, Rosa Scala, Maya Mukadam, Yuezhou Chen, Courtney Frazier, Nathaniel W York, Robert C Tryon, Gretchen A Meyer, Colin G Nichols

2020-Current year OA Pubs

Cantu syndrome (CS) is a rare disease caused by gain-of-function (GOF) mutations of Kir6.1 or SUR2 subunits of ATP-sensitive potassium (KATP) channels. CS patients with SUR2 and Kir6.1 variants display a similar constellation of symptoms, including muscle weakness and fatigue. The effects of CS mutations on skeletal muscle KATP channels, and any consequent direct effects on contractility, are currently unclear. Here, we used two knock-in mouse models of CS, respectively, carrying GOF mutations Kir6.1[V65M] or SUR2[A478V], to assess KATP channel properties and contractility in isolated fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus (SOL) muscles. Electrophysiological recordings in isolated myofibers …

Overexpression Of The Signaling Coordinator Gab2 Can Play An Important Role In Acute Myeloid Leukemia Progression, Michael H. Kramer, Stephanie N. Richardson, Yang Li, Tiankai Yin, Nichole M. Helton, Daniel R. George, Michelle Cai, Sai Mukund Ramakrishnan, Casey Ds Katerndahl, Christopher A. Miller, Timothy J. Ley

2020-Current year OA Pubs

Mutations that initiate acute myeloid leukemia (AML) can cause clonal expansion without transformation (clonal hematopoiesis). Cooperating mutations, usually in signaling genes, are needed to cause overt disease, but these may require a specific fitness state to be tolerated. Here, we show that nearly all AMLs arising in a mouse model expressing 2 common AML-initiating mutations (Dnmt3aR878H and Npm1cA) acquired a single copy amplification of chromosome 7 (chr7), followed by activating mutations in signaling genes. We show that overexpression of a single gene on chr7 (Gab2, which coordinates signaling pathways) was tolerated in the presence of the Npm1cA mutation, could accelerate …

Context-Dependent Contribution Of Peptidyl Arginine Deiminase 4 (Pad4) To Neutrophil Extracellular Trap Formation And Liver Injury In Acute And Chronic Hepatotoxicant Challenge, Gina E Capece, Amish K Patel, Daniel Hu, Tayana Roychowdhury, Bianca Hazel, Jessica Kothapalli, Noah A Mac, Frederik Denorme, Robert A Campbell, Lauren G Poole

2020-Current year OA Pubs

Neutrophils play a complex role in the pathogenesis of chronic liver disease and have been linked to both liver damage and injury resolution. Recent reports propose that neutrophils drive liver injury and fibrosis through the formation of neutrophil extracellular traps (NETs). This study tests the hypothesis that the enzyme peptidyl arginine deiminase-4 (PAD4) drives NET formation and liver fibrosis in experimental chronic liver injury. Wild-type (PAD4+/+) and PAD4-deficient (PAD4-/-) mice were chronically challenged twice weekly with carbon tetrachloride (CCl4, 1 ml/kg, i.p) or vehicle (corn oil) for 6 weeks, and samples were collected 24 h after the final challenge. In …

A Glial Circadian Gene Expression Atlas Reveals Cell-Type And Disease-Specific Reprogramming In Response To Amyloid Pathology Or Aging, Patrick W. Sheehan, Stuart B Fass, Darshan Sapkota, Sylvia Kang, Henry C Hollis, Jennifer H Lawrence, Sohui Park, Ashish Sharma, Dorothy P Schafer, Ron C Anafi, Joseph D Dougherty, John D Fryer, Erik S Musiek

2020-Current year OA Pubs

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, …

Degenerating Intervertebral Discs In The Streptozotocin-High-Fat Diet Model Of Type 2 Diabetes Show Extensive Inflammation, Christian E Gonzalez, Rachana S Vaidya, Sade W Clayton, Simon Y Tang

2020-Current year OA Pubs

The chronic inflammation observed during type 2 diabetes (T2D) is associated with spinal pathologies, including intervertebral disc (IVD) degeneration and chronic spine pain. Despite confounding factors, such as obesity, studies show that, after adjusting for age, body mass index and genetics (e.g. twins), patients with T2D experience disproportionate severity of IVD degeneration and/or back pain than individuals without T2D. We hypothesized that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts homeostasis. To test this, we evaluated two common mouse models of T2D - leptin-receptor deficient (db/db) mice and mice with a chronic high-fat diet …

Six Drivers Of Aging Identified Among Genes Differentially Expressed With Age, Ariella Coler-Reilly, Zachary Pincus, Erica L Scheller, Roberto Civitelli

2020-Current year OA Pubs

Many studies have compared gene expression in young and old samples to gain insights on aging, the primary risk factor for most chronic diseases. However, these studies only identify associations without distinguishing drivers of aging from compensatory geroprotective responses or incidental downstream effects. Here, we introduce a workflow to characterize causal effects of differentially expressed genes on lifespan. First, we performed a meta-analysis of 25 gene expression datasets comprising samples of various tissues from healthy, untreated adult mammals (humans, dogs, and rodents) at two distinct ages. Genes were ranked by the number of datasets in which they exhibited consistent differential …

Maternal Separation Disrupts Noradrenergic Control Of Adult Coping Behaviors, Chayla R Vazquez, Léa J Becker, Chao-Cheng Kuo, Solana A Cariello, Ayah N Hamdan, Ream Al-Hasani, Susan E Maloney, Jordan G Mccall

2020-Current year OA Pubs

Early life stress (ELS) profoundly impacts the brain and correlates with negative affective behaviors in adulthood. The locus coeruleus (LC), a stress-responsive brainstem nucleus that supplies most of the brain with norepinephrine (NE), is known to modulate negative affect. Using repeated maternal separation stress (MSS), we investigated the impact of ELS on the LC and stress-related behaviors in adulthood. We performed ex vivo cell-attached electrophysiology across the lifespan to reveal that MSS significantly increased LC firing during early development and adulthood but not in pre-adolescence and adolescence. We next examined potential changes in the expression of genes linked to LC …

Arousal As A Universal Embedding For Spatiotemporal Brain Dynamics, Ryan V Raut, Zachary P Rosenthal, Xiaodan Wang, Hanyang Miao, Zhanqi Zhang, Jin-Moo Lee, Marcus E Raichle, Adam Q Bauer, Steven L Brunton, Bingni W Brunton, J Nathan Kutz

2020-Current year OA Pubs

Neural activity in awake organisms shows widespread, spatiotemporally diverse correlations with behavioural and physiological measurements

Upregulation Of Adenosine A2a Receptor In Astrocytes Is Sufficient To Trigger Hippocampal Multicellular Dysfunctions And Memory Deficits, Agathe Launay, Miranda E Orr, Et Al.

2020-Current year OA Pubs

Adenosine is an ubiquitous neuromodulator that ensures cerebral homeostasis. It exerts numerous functions through the activation of G-protein-coupled adenosine receptors (ARs), in particular A

Atg-3 Limits Orsay Virus Infection In C. Elegans And Regulates Collagen Pathways, Gowri Kalugotla, Vivien Marmerstein, Lawrence A. Schriefer, Leran Wang, Stephanie A. Morrison, Luis Casorla Perez, Gary A. Silverman, Tim Schedl, Stephen C. Pak, Megan T. Baldridge

2020-Current year OA Pubs

Autophagy is an essential cellular process which functions to maintain homeostasis in response to stressors such as starvation or infection. Here, we report that a subset of autophagy factors including ATG-3 play an antiviral role in Orsay virus infection of Caenorhabditis elegans. Orsay virus infection does not modulate autophagic flux, and re-feeding after starvation limits Orsay virus infection and blocks autophagic flux, suggesting that the role of ATG-3 in Orsay virus susceptibility is independent of its role in maintaining autophagic flux. atg-3 mutants phenocopy rde-1 mutants, which have a defect in RNA interference (RNAi), in susceptibility to Orsay virus infection …

Sarm1 Inhibition Maintains Axonal Integrity After Rat Sciatic Nerve Transection And Repair, Ryan Sachar, Tony Y Lee, Aaron Diantonio, Christopher J Dy, Jason Wever, Jeff Milbrandt, David M Brogan

2020-Current year OA Pubs

PURPOSE: Sterile alpha and TlR motif containing-1 (SARM1) protein has been demonstrated to play a critical role in the initiation of Wallerian degeneration after nerve injury. The goal of this study was to assess whether blockade of SARM1 activity inhibits Wallerian degeneration following nerve transection, potentially promoting more rapid recovery of axonal function.

METHODS: An adeno-associated virus plasmid encoded with a dominant-negative SARM1 protein fused with green fluorescent protein to impair SARM1 function, was injected into 24 juvenile rats to create a SARM1 dominant-negative (SARM1-DN) phenotype. Twenty-four control rats were injected with a control plasmid expressing only green fluorescent protein. …

Basal Cell Of Origin Resolves Neuroendocrine-Tuft Lineage Plasticity In Cancer, Abbie S Ireland, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes

How Augmin Establishes The Angle Of The Microtubule Branch Site, Sophie M Travis, Jodi Kraus, Collin T Mcmanus, Kiana Golden, Rui Zhang, Sabine Petry

2020-Current year OA Pubs

How microtubules (MTs) are generated in the proper orientation is essential to understanding how the cytoskeleton organizes a cell and MT-dependent events such as cell division. In the spindle, most MTs are generated through the branching MT nucleation pathway. In this pathway, new MTs are nucleated from the side of existing MTs and oriented at a shallow angle by the branching factor augmin, ensuring that both MTs have the same polarity. Yet, how augmin binds MTs and sets the branch angle has remained unclear. Here, we report the cryo-electron microscopy structure of an augmin subcomplex on the MT. This structure …

Chromatin Profiling Identifies Putative Dual Roles For H3k27me3 In Regulating Cell Type-Specific Genes And Transposable Elements In Choanoflagellates, James M Gahan, Lily W Helfrich, Laura A Wetzel, Natarajan V Bhanu, Zuo-Fei Yuan, Benjamin A Garcia, Robert J Klose, Alex De Mendoza, David S Booth

2020-Current year OA Pubs

Chromatin-based mechanisms contribute to the exquisite regulation of gene expression during animal development. But how those mechanisms evolved remains elusive. Here we investigate chromatin regulatory features in the closest relatives of animals, choanoflagellates. In a model choanoflagellate Salpingoeca rosetta, we compare chromatin accessibility and histone modifications to gene expression. Accessible genomic regions in S. rosetta primarily correspond to gene promoters, and we find no evidence of distal gene regulatory elements that resemble enhancers deployed to regulate developmental genes in animals. Remarkably, the histone modification H3K27me3 decorates genes with cell type-specific expression, revealing a functional similarity in S. rosetta and animals. …

Enampt/Tlr4 Signaling Drives Pah Cellular Phenotypic Switching And Lung Vascular Remodeling, Mohamed Ahmed, Zhiyu Dai, Et Al.

2020-Current year OA Pubs

BACKGROUND: The attenuation of cellular phenotypic switchingdriving PAH vascular remodeling remains an unmet therapeutic need. As eNAMPT (nicotinamide phosphoribosyltransferase)/TLR4 signaling significantly contributes to PH pathobiology, an eNAMPT-neutralizing ALT-100 mAb was utilized to rescue monocrotaline (MCT) and hypoxia/Sugen (Hy/Su) preclinical PH rat models and to evaluate eNAMPT/TLR4 involvement in endothelial cell (EC), smooth muscle cell (SMC) and monocyte/macrophage phenotypic switching.

METHODS: MCT-PH or Hy/Su-PH rats received IgG or ALT-100 mAb (subQ, beginning week 4) with measurements of PH severity and lung tissue scRNAseq at day 42.

RESULTS: PH severity indices (hemodynamic, histologic, vascular remodeling) were significantly attenuated in MCT-PH and Hy/Su-PH …

Bioresponsive Hydrogel For On-Demand Nonhormonal Contraception, Giovanni M Pauletti, Pankaj Dwivedi, Ping Li, Aluet Borrego-Alvarez, Hidemi S Yamamoto, Julie Lewis, Sarah Alobaidi, Amel Ibrahim, Raina N Fichorova, Celia M Santi

2020-Current year OA Pubs

The utility of bioresponsive multifunctional hydrogel compositions for biomedical applications is rapidly increasing due to the diverse array of biological stimuli that can profoundly alter physicochemical gel properties that benefit therapeutic interventions. The purpose of this research is to explore a bioresponsive hydrogel as a drug-free bioengineering concept to fortify the natural physical contraceptive barriers at the cervicovaginal junction. The results of this research demonstrate that a hydrogel comprising 4% (

Transgenerational Adaptation To Hypoxia, Kathleen Kim, Ariel Telger, Gautam Sarkar, Sharan Surya, M Hafiz Rothi, Michael P Meers, Simon Yuan Wang, Eric Lieberman Greer

2020-Current year OA Pubs

Epigenetic inheritance alerts naïve descendants to prepare for stresses that could still be present, whereas distant descendants return to a basal state after several generations without stress. However, organisms are frequently exposed to stresses successively across generations. We found that parental hypoxia exposure increased P0 longevity, caused intergenerational lipid reduction, and elicited transgenerational fertility reduction that was dependent on generationally transmitted small RNAs. Here, we find that

Whole-Genome Sequencing Reveals Individual And Cohort Level Insights Into Chromosome 9p Syndromes., Yingxi Wang, Eleanor I Sams, Rachel Slaugh, Sandra Crocker, Emily Cordova Hurtado, Sophia Tracy, Ying-Chen Claire Hou, Christopher Markovic, Kostandin Valle, Victoria Tate, Khadija Belhassan, Elizabeth Appelbaum, Titilope Akinwe, Rodrigo T Starosta, Yang Cao, Amber Neilson, Yu Liu, Nathaniel Jensen, Reza Ghasemi, Tina Lindsay, Juana Manuel, Sophia Couteranis, Milinn Kremitzki, Jack Ustanik, Thomas Antonacci, Jeffrey K Ng, Andrew Emory, Laura Metz, Tracie Deluca, Katherine N Lyons, Toni Sinnwell, Brianne Thomeczek, Katherine A King, Christina A Gurnett, Susan K Dutcher, Catherine Gooch, Yang E Li, Amjad Horani, Michael Heinz, Richard Head, Robert Fulton, Lucinda Antonacci-Fulton, Xiaoxia Cui, Robi D Mitra, F Sessions Cole, Julie Neidich, Patricia I Dickson, Jeffrey Milbrandt, Tychele N Turner, Et Al.

2020-Current year OA Pubs

BACKGROUND: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

METHODS: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To …

Ambient Trichloroethylene Exposure And Parkinson Disease Risk In Medicare Beneficiaries, Brittany Krzyzanowski, Kassu Mehari Beyene, Jay R. Turner, Brad A. Racette

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: Trichloroethylene (TCE) is an important environmental contaminant in the United States due to widespread use industrially. Epidemiologic studies suggest that occupational exposure to TCE and TCE-contaminated drinking water may increase the risk of Parkinson disease (PD). The aim of this study was to investigate the nationwide relationship between ambient TCE and PD risk.

METHODS: We performed a nationwide, population-based, case-control study to investigate the association between incident PD in US Medicare beneficiaries aged 67 years and older in 2016-2018 and their residential exposure to ambient (outdoor) TCE in 2002. We assigned residence based on the latitude and …

Viral Oncogenes Drive Biphenotypic Lymphoproliferative Malignancy In Transgenic Mice, Daniel A Rauch, John Harding, Ancy Joseph, Lee Ratner

2020-Current year OA Pubs

Human T-cell leukemia virus type 1 (HTLV-1) is the cause of adult T-cell leukemia/lymphoma (ATLL) and viral oncogenic proteins, Tax and Hbz, are critical drivers of malignancy. Expression of both CD2 and CD20 has been described in a subset of ATLL cases. Transgenic mice were engineered to monitor lymphoma and leukemia after expression of Hbz and doxycycline-inducible Tax in activated T cells under the regulation of the human granzyme B (GZMB) promoter. These mice spontaneously developed lymphoproliferative disease characterized by the expansion and transformation of Cd2 + Cd20 + cells resulting in lymphoma and / or leukemia with involvement of …

Type I Hybrid Effectiveness-Implementation Randomised Controlled Trial To Address Intergenerational Impact Of War Trauma And Resilience Among Second-Generation Refugee Children In The Usa: Resettled Refugee Families For Healing (Rrf4h) Study Protocol, Nhial T Tutlam, Tewodros W Liyew, Theresa S Betancourt, Byron J Powell, Shenyang Guo, Mary Mckay, Fred M Ssewamala

2020-Current year OA Pubs

INTRODUCTION: Children from refugee families resettled in the USA face higher risks of serious mental health challenges compared with their native-born peers. Research shows that refugee youth in high-income countries frequently suffer from trauma-associated disorders such as post-traumatic stress disorder (PTSD), depression and anxiety. The high prevalence of trauma-associated mental health problems among these youth may be attributed to their own trauma exposure, especially if born in conflict zones, and post-resettlement challenges like poverty, acculturation difficulties, racism and discrimination. However, they may also suffer from the effects of intergenerational trauma, where parental war trauma impacts them. This study aims to …

Dendritic Atoh1a+ Cells Serve As Merkel Cell Precursors During Skin Development And Regeneration, Evan W Craig, Erik C Black, Samantha Z Fernandes, Ahlan S Ferdous, Camille E A Goo, Sheridan M Sargent, Elgene J A Quitevis, Avery Angell Swearer, Nathaniel G Yee, Jimann Shin, Lilianna Solnica-Krezel, Jeffrey P Rasmussen

2020-Current year OA Pubs

Sensory cells often adopt specific morphologies that aid in the detection of external stimuli. Merkel cells encode gentle touch stimuli in vertebrate skin and adopt a reproducible shape characterized by spiky actin-rich microvilli that emanate from the cell surface. The mechanisms by which Merkel cells acquire this stereotyped morphology from keratinocyte progenitors are unknown. Here, we establish that dendritic Merkel cells (dMCs) express atonal homolog 1a (atoh1a), extend dynamic filopodial processes, and arise in transient waves during zebrafish skin development and regeneration. We find that dMCs share molecular similarities with both basal keratinocytes and Merkel cells, yet display mesenchymal-like behaviors, …

Modeling Neurodegeneration In The Retina And Strategies For Developing Pan-Neurodegenerative Therapies, Emily L Ward, Aaron Diantonio, Et Al.

2020-Current year OA Pubs

BACKGROUND: Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma …

Antibiotic Treatment Limits Survival Of Peripheral And Bone Marrow B-Cell Populations, Lila S Sanning, Forrest C Walker, Arushana A Maknojia, Leran Wang, Haina Jin, Gowri Kalugotla, Crystal Lovato, Katherine Y King, Megan T Baldridge

2020-Current year OA Pubs

Prolonged or broad-spectrum antibiotic courses are associated with intestinal dysbiosis and cytopenias, and depletion of hematopoietic progenitor populations after antibiotics is associated with loss of peripheral immune cells, leading to increased susceptibility to systemic infections. We evaluated the bone marrow hematopoietic compartment in a murine model of antibiotic exposure. Single-cell RNA sequencing revealed a substantial and previously unrecognized depletion of bone marrow B cells at all stages of development in antibiotic-treated mice, further confirmed by flow cytometric analysis. Depletion of the microbiota was associated with rapid changes in the peripheral B-cell compartment, yet fecal microbiota transfer did not rescue either …

Dissecting Regulatory Non-Coding Gwas Loci Reveals Fibroblast Causal Genes With Pathophysiological Relevance To Heart Failure, Richard Gill, Junedh M Amrute, Kory J Lavine, Et Al.

2020-Current year OA Pubs

Heart failure is caused in part by cardiac remodeling processes that include the death of cardiac myocytes and their replacement by cardiac fibroblasts. Here, we hypothesize that cardiac fibroblasts may harbor epigenetic contexts in which heart disease-associated non-coding SNPs perturb gene expression relevant to disease. To test this, we utilized male primary cardiac fibroblasts to generate high-resolution Hi-C data and integrate it with functional genomic information to annotate and link putative distal regulatory elements in heart disease-associated loci to gene promoters. We identify several target genes with established roles in cardiac fibrosis and/or heart disease (GJA1, TBC1D32, CXCL12, IL6R, and …

Gabaergic Interneurons Contribute To The Fatal Seizure Phenotype Of Cln2 Disease Mice, Keigo Takahashi, Nicholas R. Rensing, Elizabeth M. Eultgen, Letitia L. Williams, Sophie H. Wang, Hemanth R. Nelvagal, Steven Q. Le, Marie S. Roberts, Balraj Doray, Edward B. Han, Patricia I. Dickson, Michael Wong, Mark S. Sands, Jonathan D. Cooper

2020-Current year OA Pubs

The cellular etiology of seizures in CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), remains elusive. Given that Cln2R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical GABAergic interneuron populations, we hypothesized that these 2 events might be causally related. To study the cell-autonomous effects of interneuron-specific TPP1 deficiency, we first generated transgenic mice expressing loxP-flanked lysosomal membrane-tethered TPP1 (TPP1LAMP1 mice) on the Cln2R207X/R207X genetic background, and then crossed TPP1LAMP1 mice with Vgat-Cre mice. These Vgat-Cre; TPP1LAMP1 mice accumulated storage material in cortical and striatal interneurons. Vgat-Cre; …

Transcriptional Responses Of Mouse Proximal Colon And Colonoids During Early Whipworm Infection, Hyeim Jung, Joseph F Urban, Bruce A Rosa, Makedonka Mitreva

2020-Current year OA Pubs

Trichuriasis, caused by the parasitic nematode