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Purine Biosynthesis Metabolically Constrains Intracellular Survival of Uropathogenic Escherichia coli.
Shaffer CL, Zhang EW, Dudley AG, Dixon BREA, Guckes KR, Breland EJ, Floyd KA, Casella DP, Algood HMS, Clayton DB, Hadjifrangiskou M
(2017) Infect Immun 85:
MeSH Terms: Animals, Cytoplasm, Epithelial Cells, Escherichia coli Infections, Escherichia coli Proteins, Female, Humans, Mice, Mice, Inbred C3H, Purines, Urinary Bladder, Urinary Tract Infections, Uropathogenic Escherichia coli, Virulence
Show Abstract · Added November 3, 2016
The ability to de novo synthesize purines has been associated with the intracellular survival of multiple bacterial pathogens. Uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections, undergoes a transient intracellular lifestyle during which bacteria clonally expand into multicellular bacterial communities within the cytoplasm of bladder epithelial cells. Here, we characterized the contribution of the conserved de novo purine biosynthesis-associated locus cvpA-purF to UPEC pathogenesis. Deletion of cvpA-purF, or of purF alone, abolished de novo purine biosynthesis but did not impact bacterial adherence properties in vitro or in the bladder lumen. However, upon internalization by bladder epithelial cells, UPEC deficient in de novo purine biosynthesis was unable to expand into intracytoplasmic bacterial communities over time, unless it was extrachromosomally complemented. These findings indicate that UPEC is deprived of purine nucleotides within the intracellular niche and relies on de novo purine synthesis to meet this metabolic requirement.
Copyright © 2016 American Society for Microbiology.
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14 MeSH Terms
Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis.
Scheving LA, Zhang X, Stevenson MC, Weintraub MA, Abbasi A, Clarke AM, Threadgill DW, Russell WE
(2015) Am J Physiol Gastrointest Liver Physiol 309: G942-54
MeSH Terms: Age Factors, Animals, Cell Proliferation, Cell Transformation, Neoplastic, Diethylnitrosamine, ErbB Receptors, Genotype, Hepatocytes, Liver Neoplasms, Liver Regeneration, Male, Mice, 129 Strain, Mice, Inbred C3H, Mice, Knockout, Phenotype, Phosphorylation, Receptor, ErbB-3, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added May 5, 2016
Epidermal growth factor receptor (EGFR) and ERBB3 have been implicated in hepatocellular carcinogenesis (HCC). However, it is not known whether altering the activity of either EGFR or ERBB3 affects HCC development. We now show that Egfr(Dsk5) mutant mice, which have a gain-of-function allele that increases basal EGFR kinase activity, develop spontaneous HCC by 10 mo of age. Their tumors show increased activation of EGFR, ERBB2, and ERBB3 as well as AKT and ERK1,2. Hepatocyte-specific models of EGFR and ERBB3 gene ablation were generated to evaluate how the loss of these genes affected tumor progression. Loss of either receptor tyrosine kinase did not alter liver development or regenerative liver growth following carbon tetrachloride injection. However, using a well-characterized model of HCC in which N-nitrosodiethylamine is injected into 14-day-old mice, we discovered that loss of hepatocellular ERBB3 but not EGFR, which occurred after tumor initiation, retarded liver tumor formation and cell proliferation. We found no evidence that this was due to increased apoptosis or diminished phosphatidylinositol-3-kinase activity in the ERBB3-null cells. However, the relative amount of phospho-STAT3 was diminished in tumors derived from these mice, suggesting that ERBB3 may promote HCC through STAT3 activation.
Copyright © 2015 the American Physiological Society.
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19 MeSH Terms
Lupus-Prone Mice Resist Immune Regulation and Transplant Tolerance Induction.
Stocks BT, Wilhelm AJ, Wilson CS, Marshall AF, Putnam NE, Major AS, Moore DJ
(2016) Am J Transplant 16: 334-41
MeSH Terms: Animals, Autoantibodies, Autoimmunity, Cells, Cultured, Dendritic Cells, Graft Rejection, Graft Survival, Islets of Langerhans Transplantation, Lupus Erythematosus, Systemic, Lupus Nephritis, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Inbred NOD, T-Lymphocytes, Regulatory, Transplantation Tolerance
Show Abstract · Added September 16, 2015
The strongly immunogenic environment in autoimmune diseases such as lupus may pose a stringent barrier to transplantation. Despite available murine models of lupus, transplant tolerance in this setting has yet to be fully investigated in highly penetrant genetic models of disease. Such studies are of clear clinical importance because lupus is a transplant indication in which transplanted kidneys have a substantially increased risk of rejection including a role for recurrent nephritis. In the fully penetrant B6.SLE123 mouse, we determined that CD4 T follicular helper and germinal center B cells were significantly expanded compared with healthy controls. We traced this expansion to resistance of effector CD4 T and B cells in B6.SLE123 mice to regulation by either CD4 T regulatory cells (CD4Tregs) or CD8 T regulatory cells (CD8Tregs), despite demonstrating normal function by Tregs in this strain. Finally, we determined that B6.SLE123 mice resist anti-CD45RB-mediated tolerance induction to foreign islet allografts, even in the absence of islet autoimmunity. Overall, B6.SLE123 lupus-prone mice are highly resistant to transplant tolerance induction, which provides a new model of failed tolerance in autoimmunity that may elucidate barriers to clinical transplantation in lupus through further cellular and genetic dissection.
© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
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17 MeSH Terms
Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-κB/interleukin-6 (IL-6) axis in mouse mammary cells.
Guyer RA, Macara IG
(2015) J Biol Chem 290: 8457-68
MeSH Terms: Animals, Autocrine Communication, Cell Adhesion Molecules, Cells, Cultured, Cytokine Receptor gp130, Enzyme Activation, Epithelial Cells, Female, Interleukin-6, Mammary Glands, Animal, Mice, Inbred C3H, NF-kappa B, Phosphorylation, Protein Kinase C, Protein Processing, Post-Translational, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added April 10, 2018
PAR3 suppresses tumor growth and metastasis in vivo and cell invasion through matrix in vitro. We propose that PAR3 organizes and limits multiple signaling pathways and that inappropriate activation of these pathways occurs without PAR3. Silencing Pard3 in conjunction with oncogenic activation promotes invasion and metastasis via constitutive STAT3 activity in mouse models, but the mechanism for this is unknown. We now show that loss of PAR3 triggers increased production of interleukin-6, which induces STAT3 signaling in an autocrine manner. Activation of atypical protein kinase C ι/λ (aPKCι/λ) mediates this effect by stimulating NF-κB signaling and IL-6 expression. Our results suggest that PAR3 restrains aPKCι/λ activity and thus prevents aPKCι/λ from activating an oncogenic signaling network.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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MeSH Terms
Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.
Brown JA, Ramikie TS, Schmidt MJ, Báldi R, Garbett K, Everheart MG, Warren LE, Gellért L, Horváth S, Patel S, Mirnics K
(2015) Mol Psychiatry 20: 1499-507
MeSH Terms: Animals, Behavior, Animal, Brain, Disease Models, Animal, Electrophysiology, Exploratory Behavior, Fear, Gene Silencing, Glutamate Decarboxylase, Interneurons, Ketamine, Male, Mice, Mice, Inbred C3H, Mice, Transgenic, Parvalbumins, Receptors, N-Methyl-D-Aspartate, Schizophrenia, Sensory Gating, Synaptic Transmission
Show Abstract · Added February 12, 2015
Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.
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20 MeSH Terms
Does FACS perturb gene expression?
Richardson GM, Lannigan J, Macara IG
(2015) Cytometry A 87: 166-75
MeSH Terms: Animals, Female, Flow Cytometry, Gene Expression, Gene Expression Profiling, Mammary Glands, Animal, Mice, Mice, Inbred C3H, MicroRNAs, Up-Regulation
Show Abstract · Added April 10, 2018
Fluorescence activated cell sorting is the technique most commonly used to separate primary mammary epithelial sub-populations. Many studies incorporate this technique before analyzing gene expression within specific cellular lineages. However, to our knowledge, no one has examined the effects of fluorescence activated cell sorting (FACS) separation on short-term transcriptional profiles. In this study, we isolated a heterogeneous mixture of cells from the mouse mammary gland. To determine the effects of the isolation and separation process on gene expression, we harvested RNA from the cells before enzymatic digestion, following enzymatic digestion, and following a mock FACS sort where the entire cohort of cells was retained. A strict protocol was followed to minimize disruption to the cells, and to ensure that no subpopulations were enriched or lost. Microarray analysis demonstrated that FACS causes minimal disruptions to gene expression patterns, but prior steps in the mammary cell isolation process are followed by upregulation of 18 miRNA's and rapid decreases in their predicted target transcripts. © 2015 International Society for Advancement of Cytometry.
© 2015 International Society for Advancement of Cytometry.
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MeSH Terms
The Par3-like polarity protein Par3L is essential for mammary stem cell maintenance.
Huo Y, Macara IG
(2014) Nat Cell Biol 16: 529-37
MeSH Terms: Animals, Apoptosis, Cell Adhesion Molecules, Cell Differentiation, Cell Polarity, Cell Proliferation, Cell Survival, Cells, Cultured, Female, Intracellular Signaling Peptides and Proteins, Keratin-8, Mammary Glands, Animal, Mice, Mice, Inbred C3H, Multipotent Stem Cells, Protein Binding, Protein-Serine-Threonine Kinases, RNA Interference, Signal Transduction, Tight Junctions, Transfection
Show Abstract · Added May 30, 2014
The Par polarity proteins play key roles in asymmetric division of Drosophila melanogaster stem cells; however, whether the same mechanisms control stem cells in mammals is controversial. Although necessary for mammary gland morphogenesis, Par3 is not essential for mammary stem cell function. We discovered that, instead, a previously uncharacterized protein, Par3-like (Par3L), is vital for mammary gland stem cell maintenance. Par3L function has been mysterious because, unlike Par3, it does not interact with atypical protein kinase C or the Par6 polarity protein. We found that Par3L is expressed by multipotent stem cells in the terminal end buds of murine mammary glands. Ablation of Par3L resulted in rapid and profound stem cell loss. Unexpectedly, Par3L, but not Par3, binds to the tumour suppressor protein Lkb1 and inhibits its kinase activity. This interaction is key for the function of Par3L in mammary stem cell maintenance. Our data reveal insights into a link between cell polarity proteins and stem cell survival, and uncover a biological function for Par3L.
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21 MeSH Terms
Transferrin iron starvation therapy for lethal bacterial and fungal infections.
Lin L, Pantapalangkoor P, Tan B, Bruhn KW, Ho T, Nielsen T, Skaar EP, Zhang Y, Bai R, Wang A, Doherty TM, Spellberg B
(2014) J Infect Dis 210: 254-64
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Candida albicans, Candidiasis, Cells, Cultured, Humans, Iron, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Staphylococcal Infections, Staphylococcus aureus, Transferrin, Treatment Outcome
Show Abstract · Added May 31, 2014
New strategies to treat antibiotic-resistant infections are urgently needed. We serendipitously discovered that stem cell conditioned media possessed broad antimicrobial properties. Biochemical, functional, and genetic assays confirmed that the antimicrobial effect was mediated by supra-physiological concentrations of transferrin. Human transferrin inhibited growth of gram-positive (Staphylococcus aureus), gram-negative (Acinetobacter baumannii), and fungal (Candida albicans) pathogens by sequestering iron and disrupting membrane potential. Serial passage in subtherapeutic transferrin concentrations resulted in no emergence of resistance. Infected mice treated with intravenous human transferrin had improved survival and reduced microbial burden. Finally, adjunctive transferrin reduced the emergence of rifampin-resistant mutants of S. aureus in infected mice treated with rifampin. Transferrin is a promising, novel antimicrobial agent that merits clinical investigation. These results provide proof of principle that bacterial infections can be treated in vivo by attacking host targets (ie, trace metal availability) rather than microbial targets.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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16 MeSH Terms
Cellularized cylindrical fiber/hydrogel composites for ligament tissue engineering.
Thayer PS, Dimling AF, Plessl DS, Hahn MR, Guelcher SA, Dahlgren LA, Goldstein AS
(2014) Biomacromolecules 15: 75-83
MeSH Terms: Animals, Cell Line, Hydrogel, Polyethylene Glycol Dimethacrylate, Lactic Acid, Ligaments, Mesenchymal Stem Cells, Mice, Mice, Inbred C3H, Polyglycolic Acid, Polylactic Acid-Polyglycolic Acid Copolymer, Stress, Mechanical, Tissue Engineering
Show Abstract · Added February 23, 2016
Electrospun meshes suffer from poor cell infiltration and limited thickness, which restrict their use to thin tissue applications. Herein, we demonstrate two complementary processes to overcome these limitations and achieve elastomeric composites that may be suitable for ligament repair. First, C3H10T1/2 mesenchymal stem cells were incorporated into electrospun meshes using a hybrid electrospinning/electrospraying process. Second, electrospun meshes were rolled and formed into composites with an interpenetrating polyethylene glycol (PEG) hydrogel network. Stiffer composites were formed from poly(lactic-co-glycolic acid) (PLGA) meshes, while softer and more elastic composites were formed from poly(ester-urethane urea) (PEUUR) meshes. As-spun PLGA and PEUUR rolled meshes had tensile moduli of 19.2 ± 1.9 and 0.86 ± 0.34 MPa, respectively, which changed to 11.6 ± 4.8 and 1.05 ± 0.39 MPa with the incorporation of a PEG hydrogel phase. In addition, cyclic tensile testing indicated that PEUUR-based composites deformed elastically to at least 10%. Finally, C3H10T1/2 cells incorporated into electrospun meshes survived the addition of the PEG phase and remained viable for up to 5 days. These results indicate that the fabricated cellularized composites are support cyclic mechanical conditioning, and have potential application in ligament repair.
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12 MeSH Terms
Transposon mutagenesis identifies uropathogenic Escherichia coli biofilm factors.
Hadjifrangiskou M, Gu AP, Pinkner JS, Kostakioti M, Zhang EW, Greene SE, Hultgren SJ
(2012) J Bacteriol 194: 6195-205
MeSH Terms: Animals, Bacterial Adhesion, Biofilms, Cluster Analysis, Cystitis, DNA Transposable Elements, Escherichia coli Infections, Escherichia coli Proteins, Female, Gene Expression Regulation, Bacterial, Mice, Mice, Inbred C3H, Mutagenesis, Uropathogenic Escherichia coli
Show Abstract · Added August 6, 2014
Uropathogenic Escherichia coli (UPEC), which accounts for 85% of urinary tract infections (UTI), assembles biofilms in diverse environments, including the host. Besides forming biofilms on biotic surfaces and catheters, UPEC has evolved an intracellular pathogenic cascade that culminates in the formation of biofilm-like intracellular bacterial communities (IBCs) within bladder epithelial cells. Rapid bacterial replication during IBC formation augments a build-up in bacterial numbers and persistence within the host. Relatively little is known about factors mediating UPEC biofilm formation and how these overlap with IBC formation. To address this gap, we screened a UPEC transposon mutant library in three in vitro biofilm conditions: Luria broth (LB)-polyvinyl chloride (PVC), YESCA (yeast extract-Casamino Acids)-PVC, and YESCA-pellicle that are dependent on type 1 pili (LB) and curli (YESCA), respectively. Flagella are important in all three conditions. Mutants were identified that had biofilm defects in all three conditions but had no significant effects on the expression of type 1 pili, curli, or flagella. Thus, this approach uncovered a comprehensive inventory of novel effectors and regulators that are involved in UPEC biofilm formation under multiple conditions. A subset of these mutants was found to be dramatically attenuated and unable to form IBCs in a murine model of UTI. Collectively, this study expands our insights into UPEC multicellular behavior that may provide insights into IBC formation and virulence.
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14 MeSH Terms