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The Role of the EGF Receptor in Sex Differences in Kidney Injury.
Zhang MZ, Sasaki K, Li Y, Li Z, Pan Y, Jin GN, Wang Y, Niu A, Wang S, Fan X, Chen JC, Borza C, Yang H, Pozzi A, Fogo AB, Harris RC
(2019) J Am Soc Nephrol 30: 1659-1673
MeSH Terms: Age Factors, Alleles, Animals, Castration, Cell Line, ErbB Receptors, Erlotinib Hydrochloride, Female, Gain of Function Mutation, Humans, Kidney, Male, Mice, Mice, Inbred C57BL, Middle Aged, Ovariectomy, Podocytes, Protein Kinase Inhibitors, RNA, Messenger, Renal Insufficiency, Chronic, Sex Factors, Testosterone
Show Abstract · Added August 7, 2019
BACKGROUND - Sex differences mediating predisposition to kidney injury are well known, with evidence indicating lower CKD incidence rates and slower decline in renal function in nondiabetic CKD for premenopausal women compared with men. However, signaling pathways involved have not been elucidated to date. The EGF receptor (EGFR) is widely expressed in the kidney in glomeruli and tubules, and persistent and dysregulated EGFR activation mediates progressive renal injury.
METHODS - To investigate the sex differences in response to renal injury, we examined EGFR expression in mice, in human kidney tissue, and in cultured cell lines.
RESULTS - In wild type mice, renal mRNA and protein EGFR levels were comparable in males and females at postnatal day 7 but were significantly lower in age-matched adult females than in adult males. Similar gender differences in renal EGFR expression were detected in normal adult human kidneys. In Dsk5 mutant mice with a gain-of-function allele that increases basal EGFR kinase activity, males had progressive glomerulopathy, albuminuria, loss of podocytes, and tubulointerstitial fibrosis, but female Dsk5 mice had minimal kidney injury. Oophorectomy had no effect on renal EGFR levels in female Dsk5 mice, while castration protected against the kidney injury in male Dsk5 mice, in association with a reduction in EGFR expression to levels seen in females. Conversely, testosterone increased EGFR expression and renal injury in female Dsk5 mice. Testosterone directly stimulated EGFR expression in cultured kidney cells.
CONCLUSIONS - These studies indicate that differential renal EGFR expression plays a role in the sex differences in susceptibility to progressive kidney injury that may be mediated at least in part by testosterone.
Copyright © 2019 by the American Society of Nephrology.
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22 MeSH Terms
Structural basis for influenza virus NS1 protein block of mRNA nuclear export.
Zhang K, Xie Y, Muñoz-Moreno R, Wang J, Zhang L, Esparza M, García-Sastre A, Fontoura BMA, Ren Y
(2019) Nat Microbiol 4: 1671-1679
MeSH Terms: A549 Cells, Active Transport, Cell Nucleus, Binding Sites, Cell Nucleus, Cells, Cultured, Crystallography, X-Ray, Humans, Influenza A virus, Influenza, Human, Models, Molecular, Multiprotein Complexes, Nuclear Pore Complex Proteins, Nucleocytoplasmic Transport Proteins, Protein Binding, RNA, Messenger, RNA-Binding Proteins, Viral Nonstructural Proteins
Show Abstract · Added March 3, 2020
Influenza viruses antagonize key immune defence mechanisms via the virulence factor non-structural protein 1 (NS1). A key mechanism of virulence by NS1 is blocking nuclear export of host messenger RNAs, including those encoding immune factors; however, the direct cellular target of NS1 and the mechanism of host mRNA export inhibition are not known. Here, we identify the target of NS1 as the mRNA export receptor complex, nuclear RNA export factor 1-nuclear transport factor 2-related export protein 1 (NXF1-NXT1), which is the principal receptor mediating docking and translocation of mRNAs through the nuclear pore complex via interactions with nucleoporins. We determined the crystal structure of NS1 in complex with NXF1-NXT1 at 3.8 Å resolution. The structure reveals that NS1 prevents binding of NXF1-NXT1 to nucleoporins, thereby inhibiting mRNA export through the nuclear pore complex into the cytoplasm for translation. We demonstrate that a mutant influenza virus deficient in binding NXF1-NXT1 does not block host mRNA export and is attenuated. This attenuation is marked by the release of mRNAs encoding immune factors from the nucleus. In sum, our study uncovers the molecular basis of a major nuclear function of influenza NS1 protein that causes potent blockage of host gene expression and contributes to inhibition of host immunity.
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Multiplex RNA single molecule FISH of inducible mRNAs in single yeast cells.
Li G, Neuert G
(2019) Sci Data 6: 94
MeSH Terms: In Situ Hybridization, Fluorescence, Membrane Transport Proteins, RNA, Fungal, RNA, Messenger, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Single-Cell Analysis
Show Abstract · Added February 5, 2020
Transcript levels powerfully influence cell behavior and phenotype and are carefully regulated at several steps. Recently developed single cell approaches such as RNA single molecule fluorescence in-situ hybridization (smFISH) have produced advances in our understanding of how these steps work within the cell. In comparison to single-cell sequencing, smFISH provides more accurate quantification of RNA levels. Additionally, transcript subcellular localization is directly visualized, enabling the analysis of transcription (initiation and elongation), RNA export and degradation. As part of our efforts to investigate how this type of analysis can generate improved models of gene expression, we used smFISH to quantify the kinetic expression of STL1 and CTT1 mRNAs in single Saccharomyces cerevisiae cells upon 0.2 and 0.4 M NaCl osmotic stress. In this Data Descriptor, we outline our procedure along with our data in the form of raw images and processed mRNA counts. We discuss how these data can be used to develop single cell modelling approaches, to study fundamental processes in transcription regulation and develop single cell image processing approaches.
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α-Difluoromethylornithine reduces gastric carcinogenesis by causing mutations in .
Sierra JC, Suarez G, Piazuelo MB, Luis PB, Baker DR, Romero-Gallo J, Barry DP, Schneider C, Morgan DR, Peek RM, Gobert AP, Wilson KT
(2019) Proc Natl Acad Sci U S A 116: 5077-5085
MeSH Terms: Animals, Bacterial Proteins, Carcinogenesis, DNA Damage, Eflornithine, Gene Deletion, Gene Rearrangement, Gerbillinae, Helicobacter pylori, Male, Mutation, Oxidative Stress, RNA, Messenger, Stomach Neoplasms, Virulence
Show Abstract · Added February 26, 2019
Infection by is the primary cause of gastric adenocarcinoma. The most potent virulence factor is cytotoxin-associated gene A (CagA), which is translocated by a type 4 secretion system (T4SS) into gastric epithelial cells and activates oncogenic signaling pathways. The gene encodes for a key component of the T4SS and can undergo gene rearrangements. We have shown that the cancer chemopreventive agent α-difluoromethylornithine (DFMO), known to inhibit the enzyme ornithine decarboxylase, reduces -mediated gastric cancer incidence in Mongolian gerbils. In the present study, we questioned whether DFMO might directly affect pathogenicity. We show that output strains isolated from gerbils treated with DFMO exhibit reduced ability to translocate CagA in gastric epithelial cells. Further, we frequently detected genomic modifications in the middle repeat region of the gene of output strains from DFMO-treated animals, which were associated with alterations in the CagY protein. Gerbils did not develop carcinoma when infected with a DFMO output strain containing rearranged or the parental strain in which the wild-type was replaced by with DFMO-induced rearrangements. Lastly, we demonstrate that in vitro treatment of by DFMO induces oxidative DNA damage, expression of the DNA repair enzyme MutS2, and mutations in , demonstrating that DFMO directly affects genomic stability. Deletion of abrogated the ability of DFMO to induce rearrangements directly. In conclusion, DFMO-induced oxidative stress in leads to genomic alterations and attenuates virulence.
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Tissue-Specific Differential Expression of Novel Genes and Long Intergenic Noncoding RNAs in Humans With Extreme Response to Evoked Endotoxemia.
Ferguson JF, Xue C, Gao Y, Tian T, Shi J, Zhang X, Wang Y, Li YD, Wei Z, Li M, Zhang H, Reilly MP
(2018) Circ Genom Precis Med 11: e001907
MeSH Terms: Adipose Tissue, Animals, Endotoxemia, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Immunity, Innate, Inflammation, Male, Mice, Monocytes, RNA, Long Noncoding, RNA, Messenger, Sequence Analysis, RNA
Show Abstract · Added April 2, 2019
BACKGROUND - Cytokine responses to activation of innate immunity differ between individuals, yet the genomic and tissue-specific transcriptomic determinants of inflammatory responsiveness are not well understood. We hypothesized that tissue-specific mRNA and long intergenic noncoding RNA (lincRNA) induction differs between individuals with divergent evoked inflammatory responses.
METHODS - In the GENE Study (Genetics of Evoked Response to Niacin and Endotoxemia), we performed an inpatient endotoxin challenge (1 ng/kg lipopolysaccharide [LPS]) in healthy humans. We selected individuals in the top (high responders) and bottom (low responders) extremes of inflammatory responses and applied RNA sequencing to CD14 monocytes (N=15) and adipose tissue (N=25) before and after LPS administration.
RESULTS - Although only a small number of genes were differentially expressed at baseline, there were clear differences in the magnitude of the transcriptional response post-LPS between high and low responders, with a far greater number of genes differentially expressed by endotoxemia in high responders. Furthermore, tissue responses differed during inflammation, and we found a number of tissue-specific differentially expressed lincRNAs post-LPS, which we validated. Relative to nondifferentially expressed lincRNAs, differentially expressed lincRNAs were equally likely to be nonconserved as conserved between human and mouse, indicating that conservation is not a predictor of lincRNAs associated with human inflammatory pathophysiology. Differentially expressed genes also were enriched for signals with inflammatory and cardiometabolic disease in published genome-wide association studies. CTB-41I6.2 ( AC002091.1), a nonconserved human-specific lincRNA, is one of the top lincRNAs regulated by endotoxemia in monocytes, but not in adipose tissue. Knockdown experiments in THP-1 monocytes suggest that this lincRNA enhances LPS-induced interleukin 6 ( IL6) expression in monocytes, and we now refer to this as monocyte LPS-induced lincRNA regulator of IL6 ( MOLRIL6).
CONCLUSIONS - We highlight mRNAs and lincRNAs that represent novel candidates for modulation of innate immune and metabolic responses in humans.
CLINICAL TRIAL REGISTRATION - URL: https://www.clinicaltrials.gov . Unique identifier: NCT00953667.
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Transgene-associated human growth hormone expression in pancreatic β-cells impairs identification of sex-based gene expression differences.
Stancill JS, Osipovich AB, Cartailler JP, Magnuson MA
(2019) Am J Physiol Endocrinol Metab 316: E196-E209
MeSH Terms: Animals, Female, Gene Expression, Genes, Reporter, Green Fluorescent Proteins, Human Growth Hormone, Humans, Insulin, Insulin-Secreting Cells, Male, Mice, Mice, Transgenic, Promoter Regions, Genetic, RNA, Messenger, Sex Factors, Transgenes
Show Abstract · Added December 14, 2018
Fluorescent protein reporter genes are widely used to identify and sort murine pancreatic β-cells. In this study, we compared use of the MIP-GFP transgene, which exhibits aberrant expression of human growth hormone (hGH), with a newly derived Ins2 allele that lacks hGH expression on the expression of sex-specific genes. β-Cells from MIP-GFP transgenic mice exhibit changes in the expression of 7,733 genes, or greater than half of their transcriptome, compared with β-cells from Ins2 mice. To determine how these differences might affect a typical differential gene expression study, we analyzed the effect of sex on gene expression using both reporter lines. Six hundred fifty-seven differentially expressed genes were identified between male and female β-cells containing the Ins2 allele. Female β-cells exhibit higher expression of Xist, Tmed9, Arpc3, Eml2, and several islet-enriched transcription factors, including Nkx2-2 and Hnf4a, whereas male β-cells exhibited a generally higher expression of genes involved in cell cycle regulation. In marked contrast, the same male vs. female comparison of β-cells containing the MIP-GFP transgene revealed only 115 differentially expressed genes, and comparison of the 2 lists of differentially expressed genes revealed only 17 that were common to both analyses. These results indicate that 1) male and female β-cells differ in their expression of key transcription factors and cell cycle regulators and 2) the MIP-GFP transgene may attenuate sex-specific differences that distinguish male and female β-cells, thereby impairing the identification of sex-specific variations.
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16 MeSH Terms
Role of a Stem-Loop Structure in Transcript Stability.
Loh JT, Lin AS, Beckett AC, McClain MS, Cover TL
(2019) Infect Immun 87:
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, DNA, Bacterial, Helicobacter Infections, Helicobacter pylori, Humans, Mutagenesis, Site-Directed, RNA Stability, RNA, Messenger
Show Abstract · Added February 7, 2019
CagA is a secreted effector protein that contributes to gastric carcinogenesis. Previous studies showed that there is variation among strains in the steady-state levels of CagA and that a strain-specific motif downstream of the transcriptional start site (the +59 motif) is associated with both high levels of CagA and premalignant gastric histology. The 5' untranslated region contains a predicted stem-loop-forming structure adjacent to the +59 motif. In the current study, we investigated the effect of the +59 motif and the adjacent stem-loop on transcript levels and mRNA stability. Using site-directed mutagenesis, we found that mutations predicted to disrupt the stem-loop structure resulted in decreased steady-state levels of both the transcript and the CagA protein. Additionally, these mutations resulted in a decreased mRNA half-life. Mutagenesis of the +59 motif without altering the stem-loop structure resulted in reduced steady-state transcript and CagA protein levels but did not affect transcript stability. transcript stability was not affected by increased sodium chloride concentrations, an environmental factor known to augment transcript levels and CagA protein levels. These results indicate that both a predicted stem-loop structure and a strain-specific +59 motif in the 5' untranslated region influence the levels of expression.
Copyright © 2019 American Society for Microbiology.
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Targeted Imaging of VCAM-1 mRNA in a Mouse Model of Laser-Induced Choroidal Neovascularization Using Antisense Hairpin-DNA-Functionalized Gold-Nanoparticles.
Uddin MI, Kilburn TC, Yang R, McCollum GW, Wright DW, Penn JS
(2018) Mol Pharm 15: 5514-5520
MeSH Terms: Animals, Biomarkers, Choroid, Choroidal Neovascularization, Disease Models, Animal, Fluorescent Dyes, Gold, Humans, Intravital Microscopy, Lasers, Male, Metal Nanoparticles, Mice, Mice, Inbred C57BL, Molecular Imaging, Molecular Probes, Oligodeoxyribonucleotides, Antisense, Optical Imaging, RNA, Messenger, Vascular Cell Adhesion Molecule-1, Wet Macular Degeneration
Show Abstract · Added April 10, 2019
Mouse laser-induced choroidal neovascularization (mouse LCNV) recapitulates the "wet" form of human age-related macular degeneration (AMD). Vascular cell adhesion molecule-1 (VCAM-1) is a known inflammatory biomarker, and it increases in the choroidal neovascular tissues characteristic of this experimental model. We have designed and constructed gold nanoparticles (AuNPs) functionalized with hairpin-DNA that incorporates an antisense sequence complementary to VCAM-1 mRNA (AS-VCAM-1 hAuNPs) and tested them as optical imaging probes. The 3' end of the hairpin is coupled to a near-infrared fluorophore that is quenched by the AuNP surface via Förster resonance energy transfer (FRET). Hybridization of the antisense sequence to VCAM-1 mRNA displaces the fluorophore away from the AuNP surface, inducing fluorescent activity. In vitro testing showed that hAuNPs hybridize to an exogenous complementary oligonucleotide within a pH range of 4.5-7.4, and that they are stable at reduced pH. LCNV mice received tail-vein injections of AS-VCAM-1 hAuNPs. Hyperspectral imaging revealed the delivery of AS-VCAM-1 hAuNPs to excised choroidal tissues. Fluorescent images of CNV lesions were obtained, presumably in response to the hybridization of AS-hAuNPs to LCNV-induced VCAM-1 mRNA. This is the first demonstration of systemic delivery of hAuNPs to ocular tissues to facilitate mRNA imaging of any target.
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Adenosine A Receptor mRNA Expression by Neurons and Glia in the Auditory Forebrain.
Hackett TA
(2018) Anat Rec (Hoboken) 301: 1882-1905
MeSH Terms: Animals, Auditory Cortex, Female, Gene Expression, Geniculate Bodies, Male, Mice, Mice, Inbred C57BL, Neuroglia, Neurons, Prosencephalon, RNA, Messenger, Receptor, Adenosine A1
Show Abstract · Added March 3, 2020
In the brain, purines such as ATP and adenosine can function as neurotransmitters and co-transmitters, or serve as signals in neuron-glial interactions. In thalamocortical (TC) projections to sensory cortex, adenosine functions as a negative regulator of glutamate release via activation of the presynaptic adenosine A1 receptor (A R). In the auditory forebrain, restriction of A R-adenosine signaling in medial geniculate (MG) neurons is sufficient to extend LTP, LTD, and tonotopic map plasticity in adult mice for months beyond the critical period. Interfering with adenosine signaling in primary auditory cortex (A1) does not contribute to these forms of plasticity, suggesting regional differences in the roles of A R-mediated adenosine signaling in the forebrain. To advance understanding of the circuitry, in situ hybridization was used to localize neuronal and glial cell types in the auditory forebrain that express A R transcripts (Adora1), based on co-expression with cell-specific markers for neuronal and glial subtypes. In A1, Adora1 transcripts were concentrated in L3/4 and L6 of glutamatergic neurons. Subpopulations of GABAergic neurons, astrocytes, oligodendrocytes, and microglia expressed lower levels of Adora1. In MG, Adora1 was expressed by glutamatergic neurons in all divisions, and subpopulations of all glial classes. The collective findings imply that A R-mediated signaling broadly extends to all subdivisions of auditory cortex and MG. Selective expression by neuronal and glial subpopulations suggests that experimental manipulations of A R-adenosine signaling could impact several cell types, depending on their location. Strategies to target Adora1 in specific cell types can be developed from the data generated here. Anat Rec, 301:1882-1905, 2018. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
© 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
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PD-1 up-regulation on CD4 T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production.
Celada LJ, Kropski JA, Herazo-Maya JD, Luo W, Creecy A, Abad AT, Chioma OS, Lee G, Hassell NE, Shaginurova GI, Wang Y, Johnson JE, Kerrigan A, Mason WR, Baughman RP, Ayers GD, Bernard GR, Culver DA, Montgomery CG, Maher TM, Molyneaux PL, Noth I, Mutsaers SE, Prele CM, Peebles RS, Newcomb DC, Kaminski N, Blackwell TS, Van Kaer L, Drake WP
(2018) Sci Transl Med 10:
MeSH Terms: Adult, Aged, Animals, Bleomycin, CD4-Positive T-Lymphocytes, Cell Proliferation, Collagen Type I, Disease Models, Animal, Female, Fibroblasts, Gene Expression Regulation, Humans, Idiopathic Pulmonary Fibrosis, Interleukin-17, Male, Mice, Middle Aged, Programmed Cell Death 1 Receptor, RNA, Messenger, STAT3 Transcription Factor, Sarcoidosis, Th17 Cells, Transforming Growth Factor beta1, Up-Regulation
Show Abstract · Added March 26, 2019
Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1CD4 T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4 T cells. PD-1 T helper 17 cells are the predominant CD4 T cell subset expressing TGF-β. Coculture of PD-1CD4 T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4 T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1CD4 T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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