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1. Development of spirulina for the manufacture and oral delivery of protein therapeutics

Author

Jester, Benjamin W., Zhao, Hui, Gewe, Mesfin, Adame, Thomas, Perruzza, Lisa, Bolick, David T., Agosti, Jan, Khuong, Nhi, Kuestner, Rolf, Gamble, Caitlin, Cruickshank, Kendra, Ferrara, Jeremy, Lim, Rachelle, Paddock, Troy, Brady, Colin, Ertel, Stacey, Zhang, Miaohua, Pollock, Alex, Lee, Jamie, Xiong, Jian, Tasch, Michael, Saveria, Tracy, Doughty, David, Marshall, Jacob, Carrieri, Damian, Goetsch, Lauren, Dang, Jason, Sanjaya, Nathaniel, Fletcher, David, Martinez, Anissa, Kadis, Bryce, Sigmar, Kristjan, Afreen, Esha, Nguyen, Tammy, Randolph, Amanda, Taber, Alexandria, Krzeszowski, Ashley, Robinett, Brittney, Volkin, David B., Grassi, Fabio, Guerrant, Richard, Takeuchi, Ryo, Finrow, Brian, Behnke, Craig, and Roberts, James

Published
2022
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2. Author Correction: Development of spirulina for the manufacture and oral delivery of protein therapeutics

Author

Jester, Benjamin W., Zhao, Hui, Gewe, Mesfin, Adame, Thomas, Perruzza, Lisa, Bolick, David T., Agosti, Jan, Khuong, Nhi, Kuestner, Rolf, Gamble, Caitlin, Cruickshank, Kendra, Ferrara, Jeremy, Lim, Rachelle, Paddock, Troy, Brady, Colin, Ertel, Stacey, Zhang, Miaohua, Pollock, Alex, Lee, Jamie, Xiong, Jian, Tasch, Michael, Saveria, Tracy, Doughty, David, Marshall, Jacob, Carrieri, Damian, Goetsch, Lauren, Dang, Jason, Sanjaya, Nathaniel, Fletcher, David, Martinez, Anissa, Kadis, Bryce, Sigmar, Kristjan, Afreen, Esha, Nguyen, Tammy, Randolph, Amanda, Taber, Alexandria, Krzeszowski, Ashley, Robinett, Brittney, Volkin, David B., Grassi, Fabio, Guerrant, Richard, Takeuchi, Ryo, Finrow, Brian, Behnke, Craig, and Roberts, James

Published
2022
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7. Treatment with the reactive oxygen species scavenger EUK-207 reduces lung damage and increases survival during 1918 influenza virus infection in mice

Author

Kash, John C., Xiao, Yongli, Davis, Sally A., Walters, Kathie-Anne, Chertow, Daniel S., Easterbrook, Judith D., Dunfee, Rebecca L., Sandouk, Aline, Jagger, Brett W., Schwartzman, Louis M., Kuestner, Rolf E., Wehr, Nancy B., Huffman, Karl, Rosenthal, Rosalind A., Ozinsky, Adrian, Levine, Rodney L., Doctrow, Susan R., and Taubenberger, Jeffery K.

Published
2014
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8. Expression and manufacturing of protein therapeutics in spirulina

Author

Jester, Benjamin, primary, Zhao, Hui, additional, Gewe, Mesfin, additional, Adame, Thomas, additional, Perruzza, Lisa, additional, Bolick, David, additional, Agosti, Jan, additional, Khuong, Nhi, additional, Kuestner, Rolf, additional, Gamble, Caitlin, additional, Cruickshank, Kendra, additional, Ferrara, Jeremy, additional, Lim, Rachelle, additional, Paddock, Troy, additional, Brady, Colin, additional, Ertel, Stacey, additional, Zhang, Mia, additional, Tasch, Michael, additional, Saveria, Tracy, additional, Doughty, David, additional, Marshall, Jacob, additional, Carrieri, Damian, additional, Lee, Jamie, additional, Goetsch, Lauren, additional, Dang, Jason, additional, Sanjaya, Nathaniel, additional, Fletecher, David, additional, Martinez, Anissa, additional, Kadis, Bryce, additional, Sigmar, Kristjian, additional, Afreen, Esha, additional, Nguyen, Tammy, additional, Randolph, Amanda, additional, Taber, Alexandria, additional, Krzeszowski, Ashley, additional, Robinett, Brittney, additional, Grassi, Fabio, additional, Guerrant, Richard, additional, Spigarelli, Michael, additional, Takeuchi, Ryo, additional, Finrow, Brian, additional, Behnke, Craig, additional, and Roberts, James, additional

Published
2021
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9. Chimeric human calcitonin and glucagon receptors reveal two dissociable calcitonin interaction sites

Author

Stroop, Steven D., Kuestner, Rolf E., Serwold, Thomas F., Chen, Lennie, and Moore, Emma E.

Subjects
Calcitonin -- Research, Hormone receptors -- Research, Glucagon -- Research, Binding sites (Biochemistry) -- Research, Biological sciences, Chemistry
Abstract

Transposing the coding region for the N-terminal domains of human clacitonin (hCTR) and glucagon (hGGR) receptors results in two chimeric receptors that can be expressed as glycosylated proteins. The calcitonian receptor possess two physically dissociable hormone sites, which help in complexation between the hormone and the receptor. Salmon calcitonin binds with high affinity at one of the sites in the N-terminus of the receptor, while adenylate cyclase is activated at the second site in the C-terminus of the receptor.

Published
1995

10. Loss of inter-cellular cooperation by complete epithelial-mesenchymal transition supports favorable outcomes in basal breast cancer patients

Author

Grosse-Wilde, Anne, Kuestner, Rolf E., Skelton, Stephanie M., MacIntosh, Ellie, Fouquier d'Hérouël, Aymeric, Ertaylan, Gökhan, del Sol, Antonio, Skupin, Alexander, Huang, Sui, Grosse-Wilde, Anne, Kuestner, Rolf E., Skelton, Stephanie M., MacIntosh, Ellie, Fouquier d'Hérouël, Aymeric, Ertaylan, Gökhan, del Sol, Antonio, Skupin, Alexander, and Huang, Sui

Abstract

According to the sequential metastasis model, aggressive mesenchymal (M) metastasis-initiating cells (MICs) are generated by an epithelial-mesenchymal transition (EMT) which eventually is reversed by a mesenchymal-epithelial transition (MET) and outgrowth of life-threatening epithelial (E) macrometastases. Paradoxically, in breast cancer M signatures are linked with more favorable outcomes than E signatures, and M cells are often dispensable for metastasis in mouse models. Here we present evidence at the cellular and patient level for the cooperation metastasis model, according to which E cells are MICs, while M cells merely support E cell persistence through cooperation. We tracked the fates of co-cultured E and M clones and of fluorescent CDH1-promoter-driven cell lines reporting the E state derived from basal breast cancer HMLER cells. Cells were placed in suspension state and allowed to reattach and select an EMT cell fate. Flow cytometry, single cell and bulk gene expression analyses revealed that only pre-existing E cells generated E cells, mixed E/M populations, or stem-like hybrid E/M cells after suspension and that complete EMT manifest in M clones and CDH1-negative reporter cells resulted in loss of cell plasticity, suggesting full transdifferentiation. Mechanistically, E-M coculture experiments supported the persistence of pre-existing E cells where M cells inhibited EMT of E cells in a mutual cooperation via direct cell-cell contact. Consistently, M signatures were associated with more favorable patient outcomes compared to E signatures in breast cancer, specifically in basal breast cancer patients. These findings suggest a potential benefit of complete EMT for basal breast cancer patients.

Published
2018

12. Additional file 4: Figure S1. of Prior infection with Type A Francisella tularensis antagonizes the pulmonary transcriptional response to an aerosolized Toll-like receptor 4 agonist

Author

Kathie-Anne Walters, Olsufka, Rachael, Kuestner, Rolf, Xiagang Wu, Wang, Kai, Skerrett, Shawn, and Ozinsky, Adrian

Abstract

A. Individual contribution of MyD88 and TRIF adaptor proteins to the pulmonary transcriptional response to aerosolized E. coli LPS. Wild-type, MyD88−/−, and TRIF−/− C57BL/6 animals were exposed to aerosolized E. coli LPS and lung tissue harvested 2.5 h later for transcriptional profiling. Each column represents gene expression data from an individual experiment comparing RNA from lung tissue from an individual treated animal to pooled RNA isolated from untreated parental lines (n = 4). Sequences shown in red represent increased expression, sequences shown in green represent decreased expression and sequences in black indicate no change in expression in treated relative to control animals. Heatmap represents those sequences that are 3-fold induced (p value

Published
2015
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13. Synergy between epithelial and mesenchymal cells in breast cancer: from mammospheres to predicting patient outcomes

Author

Grosse-Wilde, Anne, d'Herouel, Aymeric, Kuestner, Rolf, Ertaylan, Gökhan, Skupin, Alexander, Huang, Sui, and Ozinsky, Adrian

Abstract

Targeting breast cancer stem cells promises to eliminate the root of metastasis and recurrence and thus to eradicate the ultimate cause of cancer-related death of patients. However, the identity of epithelial cancer stem-like is still elusive; cancer stem-like and metastasis initiating cells have been described to be either epithelial (E) or mesenchymal (M), and thus their identity appears to critically depend on the context of the analyzed cell line. Here, we have studied the heterogeneous HMLER cell line to identify the relationships between epithelial and mesenchymal cells while they are differentiated and selected under suspension culture conditions. We find that CD24+/CD44- epithelial cells and CD44+/CD24- mesenchymal cells synergize in causing the proliferation of both sub-populations, increasing mammosphere production, and causing the emergence of aggressive motile cells when replated. We observed that when grown in suspension, isolated epithelial as well as isolated mesenchymal cell populations converged towards a hybrid E/M state characterized by coexpression of genes of both lineages, from population down to the single cell level. For epithelial populations convergence at the hybrid state during growth in suspension was thus achieved by proliferation of the most mesenchymal cells resembling an epithelial to mesenchymal transition at the population level. For mesenchymal populations, the hybrid state was reached by the reverse, MET, involving proliferation of the most epithelial cells in a context dependent manner.We use these findings to resolve which genes are predictive of poor outcome in primary human breast tumors. Here we show for the first time that high expression of mesenchymal genes in luminal B/epithelial tumors predicts poor outcome of patients, whereas expression of epithelial genes in basal/mesenchymal tumors predicts poor outcome and thus increased metastasis. Therefore, functional synergy between E and M cells can explain how the tumor context determines whether a minority of mesenchymal or epithelial cells can serve as metastatic stem cells. Citation Format: Anne Grosse-Wilde, Aymeric d'Herouel, Rolf Kuestner, Gokhan Ertaylan, Alexander Skupin, Sui Huang, Adrian Ozinsky. Synergy between epithelial and mesenchymal cells in breast cancer: from mammospheres to predicting patient outcomes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1918. doi:10.1158/1538-7445.AM2014-1918

Published
2014

14. Proteomic analysis of Dhh1 complexes reveals a role for Hsp40 chaperone Ydj1 in yeast P-body assembly

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Cary, Greg A., Vinh, Dani B.H., May, Patrick, Kuestner, Rolf, Dudley, Aimée M., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Cary, Greg A., Vinh, Dani B.H., May, Patrick, Kuestner, Rolf, and Dudley, Aimée M.

Abstract

P-bodies (PB) are ribonucleoprotein (RNP) complexes that aggregate into cytoplasmic foci when cells are exposed to stress. While the conserved mRNA decay and translational repression machineries are known components of PB, how and why cells assemble RNP complexes into large foci remain unclear. Using mass spectrometry to analyze proteins immunoisolated with the core PB protein Dhh1, we show that a considerable number of proteins contain low-complexity (LC) sequences, similar to proteins highly represented in mammalian RNP granules. We also show that the Hsp40 chaperone Ydj1, which contains an LC domain and controls prion protein aggregation, is required for the formation of Dhh1-GFP foci upon glucose depletion. New classes of proteins that reproducibly coenrich with Dhh1-GFP during PB induction include proteins involved in nucleotide or amino acid metabolism, glycolysis, tRNA aminoacylation, and protein folding. Many of these proteins have been shown to form foci in response to other stresses. Finally, analysis of RNA associated with Dhh1-GFP shows enrichment of mRNA encoding the PB protein Pat1 and catalytic RNAs along with their associated mitochondrial RNA-binding proteins. Thus, global characterization of PB composition has uncovered proteins important for PB assembly and evidence suggesting an active role for RNA in PB function.

Published
2015

15. Stemness of the hybrid Epithelial/Mesenchymal State in Breast Cancer and Its Association with Poor Survival.

Author

Grosse-Wilde, Anne, Fouquier d'Hérouël, Aymeric, McIntosh, Ellie, Ertaylan, Gökhan, Skupin, Alexander, Kuestner, Rolf E., del Sol Mesa, Antonio, Walters, Kathie-Anne, Huang, Sui, Grosse-Wilde, Anne, Fouquier d'Hérouël, Aymeric, McIntosh, Ellie, Ertaylan, Gökhan, Skupin, Alexander, Kuestner, Rolf E., del Sol Mesa, Antonio, Walters, Kathie-Anne, and Huang, Sui

Abstract

Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial to mesenchymal transition (EMT) but remains highly controversial since-depending on the cell-line studied-either epithelial (E) or mesenchymal (M) markers, alone or together have been associated with stemness. Using distinct transcript expression signatures characterizing the three different E, M and hybrid E/M cell-types, our data support a novel model that links a mixed EM signature with stemness in 1) individual cells, 2) luminal and basal cell lines, 3) in vivo xenograft mouse models, and 4) in all breast cancer subtypes. In particular, we found that co-expression of E and M signatures was associated with poorest outcome in luminal and basal breast cancer patients as well as with enrichment for stem-like cells in both E and M breast cell-lines. This link between a mixed EM expression signature and stemness was explained by two findings: first, mixed cultures of E and M cells showed increased cooperation in mammosphere formation (indicative of stemness) compared to the more differentiated E and M cell-types. Second, single-cell qPCR analysis revealed that E and M genes could be co-expressed in the same cell. These hybrid E/M cells were generated by both E or M cells and had a combination of several stem-like traits since they displayed increased plasticity, self-renewal, mammosphere formation, and produced ALDH1+ progenies, while more differentiated M cells showed less plasticity and E cells showed less self-renewal. Thus, the hybrid E/M state reflecting stemness and its promotion by E-M cooperation offers a dual biological rationale for the robust association of the mixed EM signature with poor prognosis, independent of cellular origin. Together, our model explains previous paradoxical findings that breast CSCs appear to be M in luminal cell-lines but E in basal breast cancer cell-lines. Our results suggest that targeting E/M heterogen

Published
2015

18. 1918 pandemic influenza virus andStreptococcus pneumoniaeco-infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans

Author

Walters, Kathie-Anne, primary, D'Agnillo, Felice, additional, Sheng, Zong-Mei, additional, Kindrachuk, Jason, additional, Schwartzman, Louis M, additional, Kuestner, Rolf E, additional, Chertow, Daniel S, additional, Golding, Basil T, additional, Taubenberger, Jeffery K, additional, and Kash, John C, additional

Published
2015
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23. Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniae Coinfection Is Associated with Loss of Murine Lung Repair Responses

Author

Kash, John C., primary, Walters, Kathie-Anne, additional, Davis, A. Sally, additional, Sandouk, Aline, additional, Schwartzman, Louis M., additional, Jagger, Brett W., additional, Chertow, Daniel S., additional, Qi, Li, additional, Kuestner, Rolf E., additional, Ozinsky, Adrian, additional, and Taubenberger, Jeffery K., additional

Published
2011
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25. Identification of the IL-17 Receptor Related Molecule IL-17RC as the Receptor for IL-17F

Author

Kuestner, Rolf E., primary, Taft, David W., additional, Haran, Aaron, additional, Brandt, Cameron S., additional, Brender, Ty, additional, Lum, Karen, additional, Harder, Brandon, additional, Okada, Shannon, additional, Ostrander, Craig D., additional, Kreindler, James L., additional, Aujla, Shean J., additional, Reardon, Brian, additional, Moore, Margaret, additional, Shea, Pamela, additional, Schreckhise, Randall, additional, Bukowski, Thomas R., additional, Presnell, Scott, additional, Guerra-Lewis, Patricia, additional, Parrish-Novak, Julia, additional, Ellsworth, Jeff L., additional, Jaspers, Stephen, additional, Lewis, Katherine E., additional, Appleby, Mark, additional, Kolls, Jay K., additional, Rixon, Mark, additional, West, James W., additional, Gao, Zeren, additional, and Levin, Steven D., additional

Published
2007
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26. Erratum: Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice

Author

Dillon, Stacey R, primary, Sprecher, Cindy, additional, Hammond, Angela, additional, Bilsborough, Janine, additional, Rosenfeld-Franklin, Maryland, additional, Presnell, Scott R, additional, Haugen, Harald S, additional, Maurer, Mark, additional, Harder, Brandon, additional, Johnston, Janet, additional, Bort, Susan, additional, Mudri, Sherri, additional, Kuijper, Joseph L, additional, Bukowski, Tom, additional, Shea, Pamela, additional, Dong, Dennis L, additional, Dasovich, Maria, additional, Grant, Francis J, additional, Lockwood, Luann, additional, Levin, Steven D, additional, LeCiel, Cosette, additional, Waggie, Kim, additional, Day, Heather, additional, Topouzis, Stavros, additional, Kramer, Janet, additional, Kuestner, Rolf, additional, Chen, Zhi, additional, Foster, Don, additional, Parrish-Novak, Julia, additional, and Gross, Jane A, additional

Published
2005
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27. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice

Author

Dillon, Stacey R, primary, Sprecher, Cindy, additional, Hammond, Angela, additional, Bilsborough, Janine, additional, Rosenfeld-Franklin, Maryland, additional, Presnell, Scott R, additional, Haugen, Harald S, additional, Maurer, Mark, additional, Harder, Brandon, additional, Johnston, Janet, additional, Bort, Susan, additional, Mudri, Sherri, additional, Kuijper, Joseph L, additional, Bukowski, Tom, additional, Shea, Pamela, additional, Dong, Dennis L, additional, Dasovich, Maria, additional, Grant, Francis J, additional, Lockwood, Luann, additional, Levin, Steven D, additional, LeCiel, Cosette, additional, Waggie, Kim, additional, Day, Heather, additional, Topouzis, Stavros, additional, Kramer, Janet, additional, Kuestner, Rolf, additional, Chen, Zhi, additional, Foster, Don, additional, Parrish-Novak, Julia, additional, and Gross, Jane A, additional

Published
2004
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28. Protocol for the transformation and engineering of edible algae Arthrospira platensisto generate heterologous protein-expressing strains

Author

Tabakh, Hannah, Jester, Benjamin W., Zhao, Hui, Kuestner, Rolf, Khuong, Nhi, Shanitta, Chelsea, Takeuchi, Ryo, and Roberts, James

Abstract

Here, we present a protocol for harnessing the natural transformability of the edible algae Arthrospira platensis(common name: spirulina) to generate strains that express heterologous proteins. We describe the preparation of plasmids and the steps to grow A. platensis. We then detail the transformation and passage of the strains, followed by genomic DNA extraction and genotyping to assess integration of the gene of interest. This simple transformation protocol can be applied to genome manipulation of edible algae.

Published
2023
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29. IL-28, IL-29 and their class II cytokine receptor IL-28R

Author

Sheppard, Paul, primary, Kindsvogel, Wayne, additional, Xu, Wenfeng, additional, Henderson, Katherine, additional, Schlutsmeyer, Stacy, additional, Whitmore, Theodore E., additional, Kuestner, Rolf, additional, Garrigues, Ursula, additional, Birks, Carl, additional, Roraback, Jenny, additional, Ostrander, Craig, additional, Dong, Dennis, additional, Shin, Jinu, additional, Presnell, Scott, additional, Fox, Brian, additional, Haldeman, Betty, additional, Cooper, Emily, additional, Taft, David, additional, Gilbert, Teresa, additional, Grant, Francis J., additional, Tackett, Monica, additional, Krivan, William, additional, McKnight, Gary, additional, Clegg, Chris, additional, Foster, Don, additional, and Klucher, Kevin M., additional

Published
2002
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30. Expression of IL-17B in neurons and evaluation of its possible role in the chromosome 5q-linked form of Charcot–Marie–Tooth disease

Author

Moore, Emma E., primary, Presnell, Scott, additional, Garrigues, Ursula, additional, Guilbot, Angele, additional, LeGuern, Eric, additional, Smith, Deborah, additional, Yao, Lena, additional, Whitmore, Theodore E., additional, Gilbert, Teresa, additional, Palmer, Theo D., additional, Horner, Philip J., additional, and Kuestner, Rolf E., additional

Published
2002
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34. Francisella tularensis subsp. tularensis Induces a Unique Pulmonary Inflammatory Response: Role of Bacterial Gene Expression in Temporal Regulation of Host Defense Responses

Author

Walters, Kathie-Anne, Olsufka, Rachael, Kuestner, Rolf E., Cho, Ji Hoon, Li, Hong, Zornetzer, Gregory A., Wang, Kai, Skerrett, Shawn J., and Ozinsky, Adrian

Subjects
FRANCISELLA tularensis, GENE expression in bacteria, PATHOLOGY, MORTALITY, HOST-parasite relationships, IMMUNE response, MICROBIOLOGY
Abstract

Pulmonary exposure to Francisella tularensis is associated with severe lung pathology and a high mortality rate. The lack of induction of classical inflammatory mediators, including IL1-β and TNF-α, during early infection has led to the suggestion that F. tularensis evades detection by host innate immune surveillance and/or actively suppresses inflammation. To gain more insight into the host response to Francisella infection during the acute stage, transcriptomic analysis was performed on lung tissue from mice exposed to virulent (Francisella tularensis ssp tularensis SchuS4). Despite an extensive transcriptional response in the lungs of animals as early as 4 hrs post-exposure, Francisella tularensis was associated with an almost complete lack of induction of immune-related genes during the initial 24 hrs post-exposure. This broad subversion of innate immune responses was particularly evident when compared to the pulmonary inflammatory response induced by other lethal (Yersinia pestis) and non-lethal (Legionella pneumophila, Pseudomonas aeruginosa) pulmonary infections. However, the unique induction of a subset of inflammation-related genes suggests a role for dysregulation of lymphocyte function and anti-inflammatory pathways in the extreme virulence of Francisella. Subsequent activation of a classical inflammatory response 48 hrs post-exposure was associated with altered abundance of Francisella-specific transcripts, including those associated with bacterial surface components. In summary, virulent Francisella induces a unique pulmonary inflammatory response characterized by temporal regulation of innate immune pathways correlating with altered bacterial gene expression patterns. This study represents the first simultaneous measurement of both host and Francisella transcriptome changes that occur during in vivo infection and identifies potential bacterial virulence factors responsible for regulation of host inflammatory pathways. [ABSTRACT FROM AUTHOR]

Published
2013
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35. Characterization of monoclonal antibodies specific for the Vβ3 family of the human T cell receptor generated using soluble TCR β-chain

Author

Calaman, Susan D., primary, Carson, Gerald R., additional, Henry, Larry D., additional, Kubinec, Jeffrey S., additional, Kuestner, Rolf E., additional, Ahmed, Asma, additional, Wilson, Ewa M., additional, Lin, Augustine Y., additional, Rittershaus, Charles W., additional, Marsh, Henry C., additional, and Jones, Nancy H., additional

Published
1993
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37. IL-28, IL-29 and their class II cytokine receptor IL-28R.

Author

Sheppard, Paul, Kindsvogel, Wayne, Xu, Wenfeng, Henderson, Katherine, Schlutsmeyer, Stacy, Whitmore, Theodore E., Kuestner, Rolf, Garrigues, Ursula, Birks, Carl, Roraback, Jenny, Ostrander, Craig, Dong, Dennis, Shin, Jinu, Presnell, Scott, Fox, Brian, Haldeman, Betty, Cooper, Emily, Taft, David, and Gilbert, Teresa

Subjects
INTERLEUKINS, IMMUNE system
Abstract

Cytokines play a critical role in modulating the innate and adaptive immune systems. Here, we have identified from the human genomic sequence a family of three cytokines, designated interleukin 28A (IL-28A), IL-28B and IL-29, that are distantly related to type I interferons (IFNs) and the IL-10 family. We found that like type I IFNs, IL-28 and IL-29 were induced by viral infection and showed antiviral activity. However, IL-28 and IL-29 interacted with a heterodimeric class II cytokine receptor that consisted of IL-10 receptor β (IL-10Rβ) and an orphan class II receptor chain, designated IL-28Rα. This newly described cytokine family may serve as an alternative to type I IFNs in providing immunity to viral infection. [ABSTRACT FROM AUTHOR]

Published
2003
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40. Modulation of Calcitonin Binding by Calcium: Differential Effects of Divalent Cations

Author

Stroop, Steven, Moore, Emma, Kuestner, Rolf, and Thompson, Deborah

Abstract

Binding of salmon calcitonin to bovine hypothalamic membranes is enhanced about 25% by calcium with a half-maximal effect at 15 mM calcium. In contrast, membranes prepared from a cell line expressing a recombinant human calcitonin receptor show no effect of calcium under similar conditions. The hypothalamic calcitonin receptor solubilized with CHAPS detergent retains an apparent Kd of 0.3 nM for salmon calcitonin; however, binding of calcitonin to the detergent-solubilized receptor complex can be inhibited by divalent cations in order of potency Mn>Ca Sr Mg NaCl with Mn and Ca having apparent Ki's of 5 mM and 20 mM respectively. Dixon and Scatchard plots of Mn and Ca inhibition of binding to the soluble receptor complex suggest a noncompetitive mechanism of inhibition. Calcium also inhibits calcitonin binding to a detergent-solubilized recombinant human calcitonin receptor. Inhibition of calcitonin binding is observed using two independent methods for determining soluble receptor-hormone complex and inhibition is reversed by EDTA.

Published
1993
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41. The Derivation and Characterization of Stromal Cell Lines from the Bone Marrow of p53−/−Mice: New Insights into Osteoblast and Adipocyte Differentiation

Author

Thompson, Deborah L., Lum, Karen D., Nygaard, Sean C., Kuestner, Rolf E., Kelly, Katherine A., Gimble, Jeffrey M., and Moore, Emma E.

Abstract

We have derived a series of clonal cell lines from the bone marrow of p53−/−mice that represent different stages of osteoblast and adipocyte differentiation. All cell lines show indefinite growth potential (>300 population doublings) and have generation times of 12–20 h. These cell lines have been grouped into three categories. The least mature clones are heterogeneous and appear to contain a subpopulation of stem cells, which can spontaneously generate foci that contain either adipocytes or mineralizing osteoblasts. The second category of clones are homogenous and clearly correspond to mature osteoblasts because they express high levels of the anticipated osteoblastic markers in a stable fashion and cannot differentiate into adipocytes even in the presence of inducers. The clones in the third category are the most unique. Initially they appeared to correspond to mature osteoblasts because they express alkaline phosphatase in a homogenous manner, secrete type I collagen, show a significant cyclic adenosine monophosphate response to parathyroid hormone, secrete osteocalcin, and mineralize extensively after only 4–7 days. However, in contrast to the mature osteoblasts, these clones can be induced to undergo massive adipocyte differentiation, and this differentiation is accompanied by the complete loss of expression of all osteoblastic markers except alkaline phosphatase. These observations indicate that some cells that have acquired all of the characteristics of mature osteoblasts can be diverted to the adipocyte pathway. Further characterization of these clones may be particularly relevant to osteoporotic conditions where increased adipocyte formation appears to occur at the expense of osteoblast formation.

Published
1998
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42. Lethal Synergism of 2009 Pandemic H1N1 Influenza Virus and Streptococcus pneumoniaeCoinfection Is Associated with Loss of Murine Lung Repair Responses

Author

Kash, John C., Walters, Kathie-Anne, Davis, A. Sally, Sandouk, Aline, Schwartzman, Louis M., Jagger, Brett W., Chertow, Daniel S., Qi, Li, Kuestner, Rolf E., Ozinsky, Adrian, and Taubenberger, Jeffery K.

Abstract

ABSTRACTSecondary bacterial infections increase disease severity of influenza virus infections and contribute greatly to increased morbidity and mortality during pandemics. To study secondary bacterial infection following influenza virus infection, mice were inoculated with sublethal doses of 2009 seasonal H1N1 virus (NIH50) or pandemic H1N1 virus (Mex09) followed by inoculation with Streptococcus pneumoniae48 h later. Disease was characterized by assessment of weight loss and survival, titration of virus and bacteria by quantitative reverse transcription-PCR (qRT-PCR), histopathology, expression microarray, and immunohistochemistry. Mice inoculated with virus alone showed 100% survival for all groups. Mice inoculated with Mex09 plus S. pneumoniaeshowed severe weight loss and 100% mortality with severe alveolitis, denuded bronchiolar epithelium, and widespread expression of apoptosis marker cleaved caspase 3. In contrast, mice inoculated with NIH50 plus S. pneumoniaeshowed increased weight loss, 100% survival, and slightly enhanced lung pathology. Mex09-S. pneumoniaecoinfection also resulted in increased S. pneumoniaereplication in lung and bacteremia late in infection. Global gene expression profiling revealed that Mex09-S. pneumoniaecoinfection did not induce significantly more severe inflammatory responses but featured significant loss of epithelial cell reproliferation and repair responses. Histopathological examination for cell proliferation marker MCM7 showed significant staining of airway epithelial cells in all groups except Mex09-S. pneumoniae-infected mice. This study demonstrates that secondary bacterial infection during 2009 H1N1 pandemic virus infection resulted in more severe disease and loss of lung repair responses than did seasonal influenza viral and bacterial coinfection. Moreover, this study provides novel insights into influenza virus and bacterial coinfection by showing correlation of lethal outcome with loss of airway basal epithelial cells and associated lung repair responses.IMPORTANCESecondary bacterial pneumonias lead to increased disease severity and have resulted in a significant percentage of deaths during influenza pandemics. To understand the biological basis for the interaction of bacterial and viral infections, mice were infected with sublethal doses of 2009 seasonal H1N1 and pandemic H1N1 viruses followed by infection with Streptococcus pneumoniae48 h later. Only infection with 2009 pandemic H1N1 virus and S. pneumoniaeresulted in severe disease with a 100% fatality rate. Analysis of the host response to infection during lethal coinfection showed a significant loss of responses associated with lung repair that was not observed in any of the other experimental groups. This group of mice also showed enhanced bacterial replication in the lung. This study reveals that the extent of lung damage during viral infection influences the severity of secondary bacterial infections and may help explain some differences in mortality during influenza pandemics.

Published
2011
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43. Proteomic Analysis of Dhh1 Complexes Reveals a Role for Hsp40 Chaperone Ydj1 in Yeast P-Body Assembly.

Author

Cary GA, Vinh DB, May P, Kuestner R, and Dudley AM

Subjects
DEAD-box RNA Helicases chemistry, HSP40 Heat-Shock Proteins chemistry, Protein Binding, Proteome chemistry, RNA-Binding Proteins chemistry, RNA-Binding Proteins metabolism, Ribonucleoproteins chemistry, Saccharomyces cerevisiae Proteins chemistry, DEAD-box RNA Helicases metabolism, HSP40 Heat-Shock Proteins metabolism, Proteome metabolism, Ribonucleoproteins metabolism, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins metabolism
Abstract

P-bodies (PB) are ribonucleoprotein (RNP) complexes that aggregate into cytoplasmic foci when cells are exposed to stress. Although the conserved mRNA decay and translational repression machineries are known components of PB, how and why cells assemble RNP complexes into large foci remain unclear. Using mass spectrometry to analyze proteins immunoisolated with the core PB protein Dhh1, we show that a considerable number of proteins contain low-complexity sequences, similar to proteins highly represented in mammalian RNP granules. We also show that the Hsp40 chaperone Ydj1, which contains an low-complexity domain and controls prion protein aggregation, is required for the formation of Dhh1-GFP foci on glucose depletion. New classes of proteins that reproducibly coenrich with Dhh1-GFP during PB induction include proteins involved in nucleotide or amino acid metabolism, glycolysis, transfer RNA aminoacylation, and protein folding. Many of these proteins have been shown to form foci in response to other stresses. Finally, analysis of RNA associated with Dhh1-GFP shows enrichment of mRNA encoding the PB protein Pat1 and catalytic RNAs along with their associated mitochondrial RNA-binding proteins. Thus, global characterization of PB composition has uncovered proteins important for PB assembly and evidence suggesting an active role for RNA in PB function., (Copyright © 2015 Cary et al.)

Published
2015
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