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Full-Text Articles in Medicine and Health Sciences
Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Department of Pharmacology and Experimental Therapeutics Faculty Papers
Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting …
Sars-Cov-2 Viral Proteins Nsp1 And Nsp13 Inhibit Interferon Activation Through Distinct Mechanisms, Christine Vazquez, Sydnie E Swanson, Seble G Negatu, Mark Dittmar, Jesse Miller, Holly Ramage, Sara Cherry, Kellie A Jurado
Sars-Cov-2 Viral Proteins Nsp1 And Nsp13 Inhibit Interferon Activation Through Distinct Mechanisms, Christine Vazquez, Sydnie E Swanson, Seble G Negatu, Mark Dittmar, Jesse Miller, Holly Ramage, Sara Cherry, Kellie A Jurado
Department of Microbiology and Immunology Faculty Papers
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic, infecting over 43 million people and claiming over 1 million lives, with these numbers increasing daily. Therefore, there is urgent need to understand the molecular mechanisms governing SARS-CoV-2 pathogenesis, immune evasion, and disease progression. Here, we show that SARS-CoV-2 can block IRF3 and NF-κB activation early during virus infection. We also identify that the SARS-CoV-2 viral proteins NSP1 and NSP13 can block interferon activation via distinct mechanisms. NSP1 antagonizes interferon signaling by suppressing host mRNA translation, while NSP13 downregulates interferon and NF-κB promoter signaling by limiting TBK1 …
Evidence That The Density Of Self Peptide-Mhc Ligands Regulates T-Cell Receptor Signaling., Nadia Anikeeva, Dimitry Gakamsky, Jørgen Schøller, Yuri Sykulev
Evidence That The Density Of Self Peptide-Mhc Ligands Regulates T-Cell Receptor Signaling., Nadia Anikeeva, Dimitry Gakamsky, Jørgen Schøller, Yuri Sykulev
Department of Microbiology and Immunology Faculty Papers
Noncognate or self peptide-MHC (pMHC) ligands productively interact with T-cell receptor (TCR) and are always in a large access over the cognate pMHC on the surface of antigen presenting cells. We assembled soluble cognate and noncognate pMHC class I (pMHC-I) ligands at designated ratios on various scaffolds into oligomers that mimic pMHC clustering and examined how multivalency and density of the pMHCs in model clusters influences the binding to live CD8 T cells and the kinetics of TCR signaling. Our data demonstrate that the density of self pMHC-I proteins promotes their interaction with CD8 co-receptor, which plays a critical role …
Rabies Virus Infection Induces Type I Interferon Production In An Ips-1 Dependent Manner While Dendritic Cell Activation Relies On Ifnar Signaling., Elizabeth J Faul, Celestine N Wanjalla, Mehul S Suthar, Michael Gale, Christoph Wirblich, Matthias J Schnell
Rabies Virus Infection Induces Type I Interferon Production In An Ips-1 Dependent Manner While Dendritic Cell Activation Relies On Ifnar Signaling., Elizabeth J Faul, Celestine N Wanjalla, Mehul S Suthar, Michael Gale, Christoph Wirblich, Matthias J Schnell
Department of Microbiology and Immunology Faculty Papers
As with many viruses, rabies virus (RABV) infection induces type I interferon (IFN) production within the infected host cells. However, RABV has evolved mechanisms by which to inhibit IFN production in order to sustain infection. Here we show that RABV infection of dendritic cells (DC) induces potent type I IFN production and DC activation. Although DCs are infected by RABV, the viral replication is highly suppressed in DCs, rendering the infection non-productive. We exploited this finding in bone marrow derived DCs (BMDC) in order to differentiate which pattern recognition receptor(s) (PRR) is responsible for inducing type I IFN following infection …
Signaling Through Galphai2 Protein Is Required For Recruitment Of Neutrophils For Antibody-Mediated Elimination Of Larval Strongyloides Stercoralis In Mice., Udaikumar M. Padigel, Louis Stein, Kevin Redding, James J. Lee, Thomas J. Nolan, Gerhard A. Schad, Lutz Birnbaumer, David Abraham
Signaling Through Galphai2 Protein Is Required For Recruitment Of Neutrophils For Antibody-Mediated Elimination Of Larval Strongyloides Stercoralis In Mice., Udaikumar M. Padigel, Louis Stein, Kevin Redding, James J. Lee, Thomas J. Nolan, Gerhard A. Schad, Lutz Birnbaumer, David Abraham
Department of Microbiology and Immunology Faculty Papers
The heterotrimeric guanine nucleotide-binding protein Galphai2 is involved in regulation of immune responses against microbial and nonmicrobial stimuli. Galphai2-/- mice have a selectively impaired IgM response consistent with a disorder in B cell development yet have augmented T cell effector function associated with increased production of IFN-gamma and IL-4. The goal of the present study was to determine if a deficiency in the Galphai2 protein in mice would affect the protective immune response against Strongyloides stercoralis, which is IL-4-, IL-5-, and IgM-dependent. Galphai2-/- and wild-type mice were immunized and challenged with S. stercoralis larvae and analyzed for protective immune responses …
Proteolytic Release Of Cd44 Intracellular Domain And Its Role In The Cd44 Signaling Pathway., I Okamoto, Y Kawano, D Murakami, T Sasayama, N Araki, T Miki, A J Wong, H Saya
Proteolytic Release Of Cd44 Intracellular Domain And Its Role In The Cd44 Signaling Pathway., I Okamoto, Y Kawano, D Murakami, T Sasayama, N Araki, T Miki, A J Wong, H Saya
Department of Microbiology and Immunology Faculty Papers
CD44 is a widely distributed cell surface adhesion molecule and is implicated in diverse biological processes. However, the nature of intracellular signaling triggered by CD44 remains to be elucidated. Here, we show that CD44 undergoes sequential proteolytic cleavage in the ectodomain and intracellular domain, resulting in the release of a CD44 intracellular domain (ICD) fragment. Consequently, CD44ICD acts as a signal transduction molecule, where it translocates to the nucleus and activates transcription mediated through the 12-O-tetradecanoylphorbol 13-acetate-responsive element, which is found in numerous genes involved in diverse cellular processes. Expression of an uncleavable CD44 mutant as well as metalloprotease inhibitor …
Signal Transducer And Activator Of Transcription (Stat)5 Activation By Bcr/Abl Is Dependent On Intact Src Homology (Sh)3 And Sh2 Domains Of Bcr/Abl And Is Required For Leukemogenesis., M Nieborowska-Skorska, M A Wasik, A Slupianek, P Salomoni, T Kitamura, B Calabretta, T Skorski
Signal Transducer And Activator Of Transcription (Stat)5 Activation By Bcr/Abl Is Dependent On Intact Src Homology (Sh)3 And Sh2 Domains Of Bcr/Abl And Is Required For Leukemogenesis., M Nieborowska-Skorska, M A Wasik, A Slupianek, P Salomoni, T Kitamura, B Calabretta, T Skorski
Department of Microbiology and Immunology Faculty Papers
Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor-dependent myeloid precursor cells, STAT5 activation-deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined …
Expression Of Constitutively Active Raf-1 In The Mitochondria Restores Antiapoptotic And Leukemogenic Potential Of A Transformation-Deficient Bcr/Abl Mutant., P Salomoni, M A Wasik, R F Riedel, K Reiss, J K Choi, T Skorski, B Calabretta
Expression Of Constitutively Active Raf-1 In The Mitochondria Restores Antiapoptotic And Leukemogenic Potential Of A Transformation-Deficient Bcr/Abl Mutant., P Salomoni, M A Wasik, R F Riedel, K Reiss, J K Choi, T Skorski, B Calabretta
Department of Microbiology and Immunology Faculty Papers
The oncogenic BCR/ABL protein protects hematopoietic cells from apoptosis induced by growth factor deprivation, but the mechanisms are only partially understood. A BCR/ABL mutant lacking amino acids 176-426 in the BCR domain (p185DeltaBCR) failed to protect interleukin 3-deprived 32Dcl3 myeloid precursor cells from apoptosis, although it possessed tyrosine kinase activity and was capable of activating the Ras-Raf-MAP kinase pathway. Compared to p185 wild-type transfectants, p185DeltaBCR-transfected cells showed markedly reduced levels of Bcl-2 and expressed the hypophosphorylated, proapoptotic form of BAD. Bcl-2 expression in the mitochondrial fraction of p185DeltaBCR cells was also markedly diminished and mitochondrial RAF was undetectable. In p185DeltaBCR …