@article{sai_nakanishi_scofield_tokarz_linder_cohen_ninomiya-tsuji_2023, title={Aberrantly activated TAK1 links neuroinflammation and neuronal loss in Alzheimer?s disease mouse models}, volume={136}, ISSN={["1477-9137"]}, url={http://dx.doi.org/10.1242/jcs.260102}, DOI={10.1242/jcs.260102}, abstractNote={ABSTRACT Neuroinflammation is causally associated with Alzheimer's disease (AD) pathology. Reactive glia cells secrete various neurotoxic factors that impair neuronal homeostasis eventually leading to neuronal loss. Although the glial activation mechanism in AD has been relatively well studied, how it perturbs intraneuronal signaling, which ultimately leads to neuronal cell death, remains poorly understood. Here, we report that compound stimulation with the neurotoxic factors TNF and glutamate aberrantly activates neuronal TAK1 (also known as MAP3K7), which promotes the pathogenesis of AD in mouse models. Glutamate-induced Ca2+ influx shifts TNF signaling to hyper-activate TAK1 enzymatic activity through Ca2+/calmodulin-dependent protein kinase II, which leads to necroptotic cellular damage. Genetic ablation and pharmacological inhibition of TAK1 ameliorated AD-associated neuronal loss and cognitive impairment in the AD model mice. Our findings provide a molecular mechanism linking cytokines, Ca2+ signaling and neuronal necroptosis in AD.}, number={6}, journal={JOURNAL OF CELL SCIENCE}, publisher={The Company of Biologists}, author={Sai, Kazuhito and Nakanishi, Aoi and Scofield, Kimberly M. and Tokarz, Debra A. and Linder, Keith E. and Cohen, Todd J. and Ninomiya-Tsuji, Jun}, year={2023}, month={Mar} } @article{krane_shockley_malarkey_miller_miller_tokarz_jensen_janardhan_breen_mariani_2022, title={Inter-pathologist agreement on diagnosis, classification and grading of canine glioma}, volume={7}, ISSN={["1476-5829"]}, url={https://doi.org/10.1111/vco.12853}, DOI={10.1111/vco.12853}, abstractNote={AbstractHistopathological evaluation of tumours is a subjective process, but studies of inter‐pathologist agreement are uncommon in veterinary medicine. The Comparative Brain Tumour Consortium (CBTC) recently published diagnostic criteria for canine gliomas. Our objective was to assess the degree of inter‐pathologist agreement on intracranial canine gliomas, utilising the CBTC diagnostic criteria in a cohort of eighty‐five samples from dogs with an archival diagnosis of intracranial glioma. Five pathologists independently reviewed H&E and immunohistochemistry sections and provided a diagnosis and grade. Percentage agreement and kappa statistics were calculated to measure inter‐pathologist agreement between pairs and amongst the entire group. A consensus diagnosis of glioma subtype and grade was achieved for 71/85 (84%) cases. For these cases, percentage agreement on combined diagnosis (subtype and grade), subtype only and grade only were 66%, 80% and 82%, respectively. Kappa statistics for the same were 0.466, 0.542 and 0.516, respectively. Kappa statistics for oligodendroglioma, astrocytoma and undefined glioma were 0.585, 0.566 and 0.280 and were 0.516 for both low‐grade and high‐grade tumours. Kappa statistics amongst pairs of pathologists for combined diagnosis varied from 0.352 to 0.839. 8 % of archival oligodendrogliomas and 61% of archival astrocytomas were reclassified as another entity after review. Inter‐pathologist agreement utilising CBTC guidelines for canine glioma was moderate overall but varied from fair to almost perfect between pairs of pathologists. Agreement was similar for oligodendrogliomas and astrocytomas but lower for undefined gliomas. These results are similar to pathologist agreement in human glioma studies and with other tumour entities in veterinary medicine.}, journal={VETERINARY AND COMPARATIVE ONCOLOGY}, author={Krane, Gregory A. and Shockley, Keith R. and Malarkey, David E. and Miller, Andrew D. and Miller, C. Ryan and Tokarz, Debra A. and Jensen, Heather L. and Janardhan, Kyathanahalli S. and Breen, Matthew and Mariani, Christopher L.}, year={2022}, month={Jul} } @article{krane_carly a. o'dea_malarkey_miller_miller_tokarz_jensen_janardhan_shockley_flagler_et al._2021, title={Immunohistochemical evaluation of immune cell infiltration in canine gliomas}, volume={7}, ISSN={["1544-2217"]}, DOI={10.1177/03009858211023946}, abstractNote={Evasion of the immune response is an integral part of the pathogenesis of glioma. In humans, important mechanisms of immune evasion include recruitment of regulatory T cells (Tregs) and polarization of macrophages toward an M2 phenotype. Canine glioma has a robust immune cell infiltrate that has not been extensively characterized. The purpose of this study was to determine the distribution of immune cells infiltrating spontaneous intracranial canine gliomas. Seventy-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry for CD3, forkhead box 3 (FOXP3), CD20, Iba1, calprotectin (Mac387), CD163, and indoleamine 2,3-dioxygenase (IDO). Immune cell infiltration was present in all tumors. Low-grade and high-grade gliomas significantly differed in the numbers of FoxP3+ cells, Mac387+ cells, and CD163+ cells ( P = .006, .01, and .01, respectively). Considering all tumors, there was a significant increase in tumor area fraction of CD163 compared to Mac387 ( P < .0001), and this ratio was greater in high-grade tumors than in low-grade tumors ( P = .005). These data warrant further exploration into the roles of macrophage repolarization or Treg interference therapy in canine glioma.}, journal={VETERINARY PATHOLOGY}, author={Krane, Gregory A. and Carly A. O'Dea and Malarkey, David E. and Miller, Andrew D. and Miller, C. Ryan and Tokarz, Debra A. and Jensen, Heather L. and Janardhan, Kyathanahalli S. and Shockley, Keith R. and Flagler, Norris and et al.}, year={2021}, month={Jul} } @article{reece_varikuti_kilburg-basnyat_dunigan-russell_hodge_luo_madenspacher_thomas_tokarz_tighe_et al._2021, title={Scavenger Receptor BI Attenuates IL-17A-Dependent Neutrophilic Inflammation in Asthma}, volume={64}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2020-0007OC}, abstractNote={Asthma is a common respiratory disease currently affecting more than 300 million worldwide and is characterized by airway inflammation, hyperreactivity, and remodeling. It is a heterogeneous disease consisting of corticosteroid-sensitive Th2-driven eosinophilic and corticosteroid-resistant Th17-driven neutrophilic phenotypes. One pathway recently described to regulate asthma pathogenesis is cholesterol trafficking. Scavenger receptors, in particular scavenger receptor class B type I (SR-BI), are known to direct cellular cholesterol uptake and efflux. We recently defined SR-BI functions in pulmonary host defense, however, the function of SR-BI in asthma pathogenesis is unknown. To elucidate the role of SR-BI in allergic asthma, SR-BI sufficient (SR-BI+/+) and deficient (SR-BI-/-) mice were sensitized (days 0, 7) and then challenged (days 14, 15, 16) with HDM (house dust mite) by oropharyngeal aspiration. Airway inflammation and cytokine production were quantified on day 17. When compared to SR-BI+/+ mice, HDM-challenged SR-BI-/- mice had increased bronchoalveolar lavage (BAL) neutrophils and pulmonary IL-17A production. This augmented IL-17A production in SR-BI-/- mice originated from a non-T cell source including neutrophils and alveolar macrophages. Given that SR-BI regulates adrenal steroid hormone production, we tested if the changes in SR-BI-/- mice were glucocorticoid-dependent. Indeed, SR-BI-/- mice were adrenally insufficient during HDM challenge and corticosterone replacement decreased pulmonary neutrophilia and IL-17A production in SR-BI-/- mice. Taken together, these data indicate that SR-BI dampens pulmonary neutrophilic inflammation and IL-17A production in allergic asthma at least in part by maintaining adrenal function.}, number={6}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={Reece, Sky W. and Varikuti, Sanjay and Kilburg-Basnyat, Brita and Dunigan-Russell, Katelyn and Hodge, Myles X. and Luo, Bin and Madenspacher, Jennifer H. and Thomas, Seddon Y. and Tokarz, Debra A. and Tighe, Robert M. and et al.}, year={2021}, month={Jun}, pages={698–708} } @article{yaeger_reece_kilburg-basnyat_hodge_pal_dunigan-russell_luo_you_bonner_spangenburg_et al._2021, title={Sex Differences in Pulmonary Eicosanoids and Specialized Pro-Resolving Mediators in Response to Ozone Exposure}, volume={183}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfab081}, abstractNote={Abstract Ozone (O3) is a criteria air pollutant known to increase the morbidity and mortality of cardiopulmonary diseases. This occurs through a pulmonary inflammatory response characterized by increased recruitment of immune cells into the airspace, pro-inflammatory cytokines, and pro-inflammatory lipid mediators. Recent evidence has demonstrated sex-dependent differences in the O3-induced pulmonary inflammatory response. However, it is unknown if this dimorphic response is evident in pulmonary lipid mediator metabolism. We hypothesized that there are sex-dependent differences in lipid mediator production following acute O3 exposure. Male and female C57BL/6J mice were exposed to 1 part per million O3 for 3 h and were necropsied at 6 or 24 h following exposure. Lung lavage was collected for cell differential and total protein analysis, and lung tissue was collected for mRNA analysis, metabololipidomics, and immunohistochemistry. Compared with males, O3-exposed female mice had increases in airspace neutrophilia, neutrophil chemokine mRNA, pro-inflammatory eicosanoids such as prostaglandin E2, and specialized pro-resolving mediators (SPMs), such as resolvin D5 in lung tissue. Likewise, precursor fatty acids (arachidonic and docosahexaenoic acid; DHA) were increased in female lung tissue following O3 exposure compared with males. Experiments with ovariectomized females revealed that loss of ovarian hormones exacerbates pulmonary inflammation and injury. However, eicosanoid and SPM production were not altered by ovariectomy despite depleted pulmonary DHA concentrations. Taken together, these data indicate that O3 drives an increased pulmonary inflammatory and bioactive lipid mediator response in females. Furthermore, ovariectomy increases susceptibility to O3-induced pulmonary inflammation and injury, as well as decreases pulmonary DHA concentrations.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Yaeger, Michael J. and Reece, Sky W. and Kilburg-Basnyat, Brita and Hodge, Miles X. and Pal, Anandita and Dunigan-Russell, Katelyn and Luo, Bin and You, Dorothy J. and Bonner, James C. and Spangenburg, Espen E. and et al.}, year={2021}, month={Sep}, pages={170–183} } @article{mohan_neequaye_malur_soliman_mcpeek_leffler_ogburn_tokarz_knudson_gharib_et al._2020, title={Matrix Metalloproteinase-12 Is Required for Granuloma Progression}, volume={11}, ISSN={["1664-3224"]}, DOI={10.3389/fimmu.2020.553949}, abstractNote={Background Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation. Methods C57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1). Results Pulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days. Conclusions The striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.}, journal={FRONTIERS IN IMMUNOLOGY}, author={Mohan, Arjun and Neequaye, Nicole and Malur, Anagha and Soliman, Eman and McPeek, Matthew and Leffler, Nancy and Ogburn, David and Tokarz, Debra A. and Knudson, Warren and Gharib, Sina A. and et al.}, year={2020}, month={Sep} } @article{bomba_sheets_valdivia_khagi_ruterbories_mariani_borst_tokarz_hingtgen_2021, title={Personalized-induced neural stem cell therapy: Generation, transplant, and safety in a large animal model}, volume={6}, ISSN={["2380-6761"]}, DOI={10.1002/btm2.10171}, abstractNote={AbstractIn this study, we take an important step toward clinical translation by generating the first canine‐induced neural stem cells (iNSCs). We explore key aspects of scale‐up, persistence, and safety of personalized iNSC therapy in autologous canine surgery models. iNSCs are a promising new approach to treat aggressive cancers of the brain, including the deadly glioblastoma. Created by direct transdifferentiation of fibroblasts, iNSCs are known to migrate through the brain, track down invasive cancer foci, and deliver anticancer payloads that significantly reduce tumor burden and extend survival of tumor‐bearing mice. Here, skin biopsies were collected from canines and converted into the first personalized canine iNSCs engineered to carry TNFα‐related apoptosis‐inducing ligand (TRAIL) and thymidine kinase (TK), as well as magnetic resonance imaging (MRI) contrast agents for in vivo tracking. Time‐lapse analysis showed canine iNSCs efficiently migrate to human tumor cells, and cell viability assays showed both TRAIL and TK monotherapy markedly reduced tumor growth. Using intraoperative navigation and two delivery methods to closely mimic human therapy, canines received autologous iNSCs either within postsurgical cavities in a biocompatible matrix or via a catheter placed in the lateral ventricle. Both strategies were well tolerated, and serial MRI showed hypointense regions at the implant sites that remained stable through 86 days postimplant. Serial fluid sample testing following iNSC delivery showed the bimodal personalized therapy was well tolerated, with no iNSC‐induced abnormal tissue pathology. Overall, this study lays an important foundation as this promising personalized cell therapy advances toward human patient testing.}, number={1}, journal={BIOENGINEERING & TRANSLATIONAL MEDICINE}, author={Bomba, Hunter N. and Sheets, Kevin T. and Valdivia, Alain and Khagi, Simon and Ruterbories, Laura and Mariani, Christopher L. and Borst, Luke B. and Tokarz, Debra A. and Hingtgen, Shawn D.}, year={2021}, month={Jan} } @article{mcpeek_malur_tokarz_lertpiriyapong_gowdy_murray_wingard_fessler_barna_thomassen_2019, title={Alveolar Macrophage ABCG1 Deficiency Promotes Pulmonary Granulomatous Inflammation}, volume={61}, ISSN={["1535-4989"]}, DOI={10.1165/rcmb.2018-0365OC}, abstractNote={Pulmonary granuloma formation is a complex and poorly understood response to inhaled pathogens and particulate matter. To explore the mechanisms of pulmonary granuloma formation and maintenance our laboratory has developed a multi-wall carbon nanotube (MWCNT) induced murine model of chronic granulomatous inflammation. We have demonstrated that the MWCNT model closely mimics pulmonary sarcoidosis pathophysiology, including the deficiency of alveolar macrophage ATP-binding cassette (ABC) lipid transporters ABCA1 and ABCG1. We hypothesized that deficiency of alveolar macrophage ABCA1 and ABCG1 would promote pulmonary granuloma formation and inflammation. To test this hypothesis, the effects of MWCNT instillation were evaluated in ABCA1, ABCG1 and ABCA1/ABCG1 myeloid-specific knockout mice. Histological examination revealed significantly larger pulmonary granulomas in ABCG1-KO and ABCA1/ABCG1 double knockout animals when compared to wild-type animals. Evaluation of bronchoalveolar lavage cells indicated increased expression of CCL2 and osteopontin, genes shown to be involved in the formation and maintenance of pulmonary granulomas. Single deficiency of alveolar macrophage ABCA1 did not affect MWCNT induced granuloma formation or pro-inflammatory gene expression. These observations indicate that the deficiency of alveolar macrophage ABCG1 promotes pulmonary granulomatous inflammation and that this is augmented by additional deletion of ABCA1.}, number={3}, journal={AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY}, author={McPeek, Matthew and Malur, Anagha and Tokarz, Debra A. and Lertpiriyapong, Kvin and Gowdy, Kymberly M. and Murray, Gina and Wingard, Christopher J. and Fessler, Michael B. and Barna, Barbara P. and Thomassen, Mary Jane}, year={2019}, month={Sep}, pages={332–340} } @article{schreeg_evans_allen_lewis_luckring_evola_richard_piner_thompson_adin_et al._2019, title={Cardiac Leiomyosarcoma in a Cat Presenting for Bilateral Renal Neoplasia}, volume={168}, ISSN={["1532-3129"]}, DOI={10.1016/j.jcpa.2019.02.005}, abstractNote={A 10-year-old neutered female domestic longhair cat was presented to a tertiary care veterinary hospital for evaluation of a right renal mass that was identified incidentally on abdominal radiographs and classified further as a sarcoma based on fine needle aspiration cytology. Further diagnostic workup, including ultrasound and cytology, identified a sarcoma in the left kidney. After approximately 1 month of conservative medical management, the clinical condition deteriorated and the cat was humanely destroyed. Post-mortem examination confirmed bilateral renal masses with multifocal infarction and extensive necrosis, and further identified a large mass at the apex of the heart as well as multiple pulmonary nodules. Microscopical examination of the masses identified a population of poorly-differentiated neoplastic spindle cells, consistent with sarcoma. Immunohistochemically, the neoplastic cells expressed smooth muscle actin and muscle-specific actin, but were negative for myoglobin and factor VIII. Phosphotungstic acid-haematoxylin staining was unable to identify cross-striations in the neoplastic cells. Based on these results and the pattern of lesion distribution, the cat was diagnosed with cardiac leiomyosarcoma with pulmonary and bilateral renal metastasis.}, journal={JOURNAL OF COMPARATIVE PATHOLOGY}, author={Schreeg, M. E. and Evans, B. J. and Allen, J. and Lewis, M. C. and Luckring, E. and Evola, M. and Richard, D. K. and Piner, K. and Thompson, E. M. and Adin, D. B. and et al.}, year={2019}, month={Apr}, pages={19–24} } @article{friedenberg_vansteenkiste_yost_treeful_meurs_tokarz_olby_2018, title={A de novo mutation in the EXT2 gene associated with osteochondromatosis in a litter of American Staffordshire Terriers}, volume={32}, ISSN={0891-6640}, url={http://dx.doi.org/10.1111/jvim.15073}, DOI={10.1111/jvim.15073}, abstractNote={BackgroundWe aimed to identify mutations associated with osteochondromatosis in a litter of American Staffordshire Terrier puppies.HypothesisWe hypothesized that the associated mutation would be located in a gene that causes osteochondromatosis in humans.AnimalsA litter of 9 American Staffordshire puppies, their sire and dam, 3 of 4 grandparents, 26 healthy unrelated American Staffordshire Terriers, and 154 dogs of 27 different breeds.MethodsWhole genome sequencing was performed on the proband, and variants were compared against polymorphisms derived from 154 additional dogs across 27 breeds, as well as single nucleotide polymorphism database 146. One variant was selected for follow‐up sequencing. Parentage and genetic mosaicism were evaluated across the litter.ResultsWe found 56,301 genetic variants unique to the proband. Eleven variants were located in or near the gene exostosin 2 (EXT2), which is strongly associated with osteochondromatosis in humans. One heterozygous variant (c.969C > A) is predicted to result in a stop codon in exon 5 of the gene. Sanger sequencing identified the identical mutation in all affected offspring. The mutation was absent in the unaffected offspring, both parents, all available grandparents, and 26 healthy unrelated American Staffordshire Terriers.Conclusions and Clinical ImportanceThese findings represent the first reported mutation associated with osteochondromatosis in dogs. Because this mutation arose de novo, the identical mutation is unlikely to be the cause of osteochondromatosis in other dogs. However, de novo mutations in EXT2 are common in humans with osteochondromatosis, and by extension, it is possible that dogs with osteochondromatosis could be identified by sequencing the entire EXT2 gene.}, number={3}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Friedenberg, Steven G. and Vansteenkiste, Daniella and Yost, Oriana and Treeful, Amy E. and Meurs, Kathryn M. and Tokarz, Debra A. and Olby, Natasha J.}, year={2018}, month={Feb}, pages={986–992} } @article{messenger_hall_jima_house_tam_tokarz_smart_2018, title={C/EBPβ deletion in oncogenic Ras skin tumors is a synthetic lethal event}, volume={9}, ISSN={2041-4889}, url={http://dx.doi.org/10.1038/S41419-018-1103-Y}, DOI={10.1038/s41419-018-1103-y}, abstractNote={AbstractTherapeutic targeting of specific genetic changes in cancer has proven to be an effective therapy and the concept of synthetic lethality has emerged. CCAAT/enhancer-binding protein-β (C/EBPβ), a basic leucine zipper transcription factor, has important roles in cellular processes including differentiation, inflammation, survival, and energy metabolism. Using a genetically engineered mouse model, we report that the deletion C/EBPβ in pre-existing oncogenic Ha-Ras mouse skin tumors in vivo resulted in rapid tumor regression. Regressing tumors exhibited elevated levels of apoptosis and p53 protein/activity, while adjacent C/EBPβ-deleted skin did not. These results indicate that the deletion of C/EBPβ de-represses p53 in oncogenic Ras tumors but not in normal wild-type Ras keratinocytes, and that C/EBPβ is essential for survival of oncogenic Ras tumors. Co-deletion of C/EBPβ and p53 in oncogenic Ras tumors showed p53 is required for tumor regression and elevated apoptosis. In tumors, loss of a pathway that confers adaptability to a stress phenotype of cancer/tumorigenesis, such as DNA damage, could result in selective tumor cell killing. Our results show that oncogenic Ras tumors display a significant DNA damage/replicative stress phenotype and these tumors have acquired a dependence on C/EBPβ for their survival. RNAseq data analysis of regressing tumors deleted of C/EBPβ indicates a novel interface between p53, type-1 interferon response, and death receptor pathways, which function in concert to produce activation of extrinsic apoptosis pathways. In summary, the deletion of C/EBPβ in oncogenic Ras skin tumors is a synthetic lethal event, making it a promising target for future potential anticancer therapies.}, number={11}, journal={Cell Death & Disease}, publisher={Springer Science and Business Media LLC}, author={Messenger, Zachary J. and Hall, Jonathan R. and Jima, Dereje D. and House, John S. and Tam, Hann W. and Tokarz, Debra A. and Smart, Robert C.}, year={2018}, month={Oct} } @article{mcpeek_malur_tokarz_murray_barna_thomassen_2018, title={PPAR-gamma pathways attenuate pulmonary granuloma formation in a carbon nanotube induced murine model of sarcoidosis}, volume={503}, ISSN={["1090-2104"]}, DOI={10.1016/j.bbrc.2018.06.061}, abstractNote={Peroxisome proliferator activated receptor gamma (PPARγ), a ligand activated nuclear transcription factor, is constitutively expressed in alveolar macrophages of healthy individuals. PPARγ deficiencies have been noted in several lung diseases including the alveolar macrophages of pulmonary sarcoidosis patients. We have previously described a murine model of multiwall carbon nanotubes (MWCNT) induced pulmonary granulomatous inflammation which bears striking similarities to pulmonary sarcoidosis, including the deficiency of alveolar macrophage PPARγ. Further studies demonstrate alveolar macrophage PPARγ deficiency exacerbates MWCNT-induced pulmonary granulomas. Based on these observations we hypothesized that activation of PPARγ via administration of the PPARγ-specific ligand rosiglitazone would limit MWCNT-induced granuloma formation and promote PPARγ-dependent pathways. Results presented here show that rosiglitazone significantly limits the frequency and severity of MWCNT-induced pulmonary granulomas. Furthermore, rosiglitazone attenuates alveolar macrophage NF-κB activity and downregulates the expression of the pro-inflammatory mediators, CCL2 and osteopontin. PPARγ activation via rosiglitazone also prevents the MWCNT-induced deficiency of PPARγ-regulated ATP-binding cassette lipid transporter-G1 (ABCG1) expression. ABCG1 is crucial to pulmonary lipid homeostasis. ABCG1 deficiency results in lipid accumulation which promotes pro-inflammatory macrophage activation. Our results indicate that restoration of homeostatic ABCG1 levels by rosiglitazone correlates with both reduced pulmonary lipid accumulation, and decreased alveolar macrophage activation. These data confirm and further support our previous observations that PPARγ pathways are critical in regulating MWCNT-induced pulmonary granulomatous inflammation.}, number={2}, journal={BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS}, author={McPeek, Matthew and Malur, Anagha and Tokarz, Debra A. and Murray, Gina and Barna, Barbara P. and Thomassen, Mary Jane}, year={2018}, month={Sep}, pages={684–690} } @article{duke_thompson_ihrie_taylor-just_ash_shipkowski_hall_tokarz_cesta_hubbs_et al._2018, title={Role of p53 in the chronic pulmonary immune response to tangled or rod-like multi-walled carbon nanotubes}, volume={12}, ISSN={["1743-5404"]}, DOI={10.1080/17435390.2018.1502830}, abstractNote={Abstract The fiber-like shape of multi-walled carbon nanotubes (MWCNTs) is reminiscent of asbestos, suggesting they pose similar health hazards when inhaled, including pulmonary fibrosis and mesothelioma. Mice deficient in the tumor suppressor p53 are susceptible to carcinogenesis. However, the chronic pathologic effect of MWCNTs delivered to the lungs of p53 heterozygous (p53+/−) mice has not been investigated. We hypothesized that p53+/− mice would be susceptible to lung tumor development after exposure to either tangled (t-) or rod-like (r-) MWCNTs. Wild-type (p53+/+) or p53+/− mice were exposed to MWCNTs (1 mg/kg) via oropharyngeal aspiration weekly over four consecutive weeks and evaluated for cellular and pathologic outcomes 11-months post-initial exposure. No lung or pleural tumors were observed in p53+/+ or p53+/− mice exposed to either t- or rMWCNTs. In comparison to tMWCNTs, the rMWCNTs induced the formation of larger granulomas, a greater number of lymphoid aggregates and greater epithelial cell hyperplasia in terminal bronchioles in both p53+/− and p53+/+ mice. A constitutively larger area of CD45R+/CD3+ lymphoid tissue was observed in p53+/− mice compared to p53+/+ mice. Importantly, p53+/− mice had larger granulomas induced by rMWCNTs as compared to p53+/+ mice. These findings indicate that a combination of p53 deficiency and physicochemical characteristics including nanotube geometry are factors in susceptibility to MWCNT-induced lymphoid infiltration and granuloma formation.}, number={9}, journal={NANOTOXICOLOGY}, author={Duke, Katherine S. and Thompson, Elizabeth A. and Ihrie, Mark D. and Taylor-Just, Alexia J. and Ash, Elizabeth A. and Shipkowski, Kelly A. and Hall, Jonathan R. and Tokarz, Debra A. and Cesta, Mark F. and Hubbs, Ann F. and et al.}, year={2018}, month={Oct}, pages={975–991} } @article{tokarz_heffelfinger_jima_gerlach_shah_rodriguez-nunez_kortum_fletcher_nordone_law_et al._2017, title={Disruption of Trim9 function abrogates macrophage motility in vivo}, volume={102}, ISSN={0741-5400 1938-3673}, url={http://dx.doi.org/10.1189/jlb.1A0816-371R}, DOI={10.1189/jlb.1a0816-371r}, abstractNote={Abstract The vertebrate immune response comprises multiple molecular and cellular components that interface to provide defense against pathogens. Because of the dynamic complexity of the immune system and its interdependent innate and adaptive functionality, an understanding of the whole-organism response to pathogen exposure remains unresolved. Zebrafish larvae provide a unique model for overcoming this obstacle, because larvae are protected against pathogens while lacking a functional adaptive immune system during the first few weeks of life. Zebrafish larvae were exposed to immune agonists for various lengths of time, and a microarray transcriptome analysis was executed. This strategy identified known immune response genes, as well as genes with unknown immune function, including the E3 ubiquitin ligase tripartite motif-9 (Trim9). Although trim9 expression was originally described as “brain specific,” its expression has been reported in stimulated human Mϕs. In this study, we found elevated levels of trim9 transcripts in vivo in zebrafish Mϕs after immune stimulation. Trim9 has been implicated in axonal migration, and we therefore investigated the impact of Trim9 disruption on Mϕ motility and found that Mϕ chemotaxis and cellular architecture are subsequently impaired in vivo. These results demonstrate that Trim9 mediates cellular movement and migration in Mϕs as well as neurons.}, number={6}, journal={Journal of Leukocyte Biology}, publisher={Wiley}, author={Tokarz, Debra A. and Heffelfinger, Amy K. and Jima, Dereje D. and Gerlach, Jamie and Shah, Radhika N. and Rodriguez-Nunez, Ivan and Kortum, Amanda N. and Fletcher, Ashley A. and Nordone, Shila K. and Law, J. McHugh and et al.}, year={2017}, month={Oct}, pages={1371–1380} } @article{chernyavskaya_mudbhary_zhang_tokarz_jacob_gopinath_sun_wang_magnani_madakashira_et al._2017, title={Loss of DNA methylation in zebrafish embryos activates retrotransposons to trigger antiviral signaling}, volume={144}, ISSN={0950-1991 1477-9129}, url={http://dx.doi.org/10.1242/dev.147629}, DOI={10.1242/dev.147629}, abstractNote={Complex cytoplasmic nucleotide sensing mechanisms can recognize foreign DNA based on a lack of methylation and initiate an immune response to clear the infection. Zebrafish embryos with global DNA hypomethylation caused by mutations in the ubiquitin-like, with PHD and RING finger domains 1 (uhrf1) or DNA methyltransferase 1 (dnmt1) genes exhibit a robust interferon induction characteristic of first line of defense against viral infection. We found that this interferon induction occurred in non-immune cells and asked whether intracellular viral sensing pathways in these cells were the trigger. RNA-seq analysis of uhrf1 and dnmt1 mutants revealed widespread induction of Class I retrotransposons and activation of cytoplasmic DNA viral sensors. Attenuating Sting, pTbk1 and, importantly, blocking reverse transcriptase activity suppressed the expression of interferon genes in uhrf1 mutants. Thus, activation of transposons in cells with global DNA hypomethylation mimics a viral infection by activating cytoplasmic DNA sensors. This suggests that antiviral pathways serve as surveillance of cells that have derepressed intragenomic parasites due to DNA hypomethylation.}, number={16}, journal={Development}, publisher={The Company of Biologists}, author={Chernyavskaya, Yelena and Mudbhary, Raksha and Zhang, Chi and Tokarz, Debra and Jacob, Vinitha and Gopinath, Smita and Sun, Xiaochen and Wang, Shuang and Magnani, Elena and Madakashira, Bhavani P. and et al.}, year={2017}, month={Jul}, pages={2925–2939} } @article{allen_gracieux_talib_tokarz_hensley_cores_vandergriff_tang_de andrade_dinh_et al._2016, title={Angiopellosis as an Alternative Mechanism of Cell Extravasation}, volume={35}, ISSN={1066-5099}, url={http://dx.doi.org/10.1002/stem.2451}, DOI={10.1002/stem.2451}, abstractNote={Abstract Stem cells possess the ability to home in and travel to damaged tissue when injected intravenously. For the cells to exert their therapeutic effect, they must cross the blood vessel wall and enter the surrounding tissues. The mechanism of extravasation injected stem cells employ for exit has yet to be characterized. Using intravital microscopy and a transgenic zebrafish line Tg(fli1a:egpf) with GFP-expressing vasculature, we documented the detailed extravasation processes in vivo for injected stem cells in comparison to white blood cells (WBCs). While WBCs left the blood vessels by the standard diapedesis process, injected cardiac and mesenchymal stem cells underwent a distinct method of extravasation that was markedly different from diapedesis. Here, the vascular wall undergoes an extensive remodeling to allow the cell to exit the lumen, while the injected cell remains distinctively passive in activity. We termed this process Angio-pello-sis, which represents an alternative mechanism of cell extravasation to the prevailing theory of diapedesis. Video Highlight: https://youtu.be/i5EI-ZvhBps}, number={1}, journal={STEM CELLS}, publisher={Wiley}, author={Allen, Tyler A. and Gracieux, David and Talib, Maliha and Tokarz, Debra A. and Hensley, M. Taylor and Cores, Jhon and Vandergriff, Adam and Tang, Junnan and de Andrade, James B.M. and Dinh, Phuong-Uyen and et al.}, year={2016}, month={Jul}, pages={170–180} } @article{kol_christopher_skorupski_tokarz_vernau_2012, title={B-cell lymphoma with plasmacytoid differentiation, atypical cytoplasmic inclusions, and secondary leukemia in a dog}, volume={42}, ISSN={0275-6382}, url={http://dx.doi.org/10.1111/vcp.12003}, DOI={10.1111/vcp.12003}, abstractNote={AbstractA 7‐year‐old male castrated Jack Russell Terrier was presented to the oncology service at the University of California–Davis Veterinary Medical Teaching Hospital for evaluation of suspected lymphoma. The dog had several enlarged lymph nodes and moderate lymphocytosis. Aspirates of an enlarged inguinal lymph node contained a bimorphic population of large immature lymphocytes and smaller cells with plasmacytoid features. Both cell types often contained a single large cytoplasmic inclusion that varied from clear to pale pink to sky blue. Cytologic changes were interpreted as most consistent with lymphoid neoplasia. Based on the predominantly mature cell morphology and some morphologic heterogeneity, the peripheral lymphocytosis was interpreted as most likely reactive in nature. However, the immunophenotype of the cells (CD20+, CD21+, CD79a+, MUM‐1+, and MHCII+) and clonality assays showed that tissue and blood lymphocytes were neoplastic B cells with clonal identity despite their different morphologic appearances. The cytoplasmic inclusions were positive with periodic acid‐Schiff and were immunoreactive for IgM and IgG. By transmission electron microscopy, inclusions consisted of aberrant rough endoplasmic reticulum; a few small Russell bodies were also noted. A final diagnosis of high‐grade B‐cell lymphoma with plasmacytoid differentiation, atypical cytoplasmic inclusions, and secondary leukemia was made. Chemotherapy was initiated, but the dog was euthanized due to severe and uncontrolled seizures 9 months after the initial diagnosis. This case extends the morphologic repertoire of canine plasmacytoid neoplasms and emphasizes their continuum with multicentric lymphoma. This case also demonstrates the need for advanced diagnostic techniques in establishing blood involvement in lymphoma in some instances.}, number={1}, journal={Veterinary Clinical Pathology}, publisher={Wiley}, author={Kol, A. and Christopher, M.M. and Skorupski, K.A. and Tokarz, D. and Vernau, W.}, year={2012}, month={Dec}, pages={40–46} } @article{yamout_tokarz_magdesian_le jeune_2012, title={Intrathoracic pulsion diverticulum in a horse}, volume={53}, journal={Canadian Veterinary Journal}, author={Yamout, S. and Tokarz, D. and Magdesian, K.G. and le Jeune, S.S.}, year={2012}, pages={408–411} } @article{tokarz_poppenga_kaae_filigenzi_lowenstine_pesavento_2011, title={Amanitin Toxicosis in Two Cats with Acute Hepatic and Renal Failure}, volume={49}, ISSN={0300-9858 1544-2217}, url={http://dx.doi.org/10.1177/0300985811429307}, DOI={10.1177/0300985811429307}, abstractNote={ Amanitin is a toxic cyclopeptide present in several species of poisonous mushrooms. Amanitin toxicosis was diagnosed in 2 cats from separate premises. Both cats initially had lethargy and vomiting, and they rapidly developed depression and neurological signs over 24–48 hours. Marked elevation of alanine aminotransferase was the primary finding, with subsequent serum chemistry values compatible with hepatic and renal failure. Histopathological findings consisted of submassive to massive acute hepatic necrosis, renal proximal tubular epithelial necrosis, and foci of necrosis and inflammation in the gastrointestinal tract. Amanitin exposure was confirmed postmortem by detection of α-amanitin in the kidney by liquid chromatography–mass spectrometry. A similar clinical course and pathological changes are reported in human and canine amanitin intoxication; however, gastrointestinal lesions are not typically described. }, number={6}, journal={Veterinary Pathology}, publisher={SAGE Publications}, author={Tokarz, D. and Poppenga, R. and Kaae, J. and Filigenzi, M. and Lowenstine, L. J. and Pesavento, P.}, year={2011}, month={Dec}, pages={1032–1035} } @article{sykes_marks_mapes_schultz_pollard_tokarz_pesavento_lindsay_foley_2010, title={Salmon Poisoning Disease in Dogs: 29 Cases}, volume={24}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.2010.0493.x}, DOI={10.1111/j.1939-1676.2010.0493.x}, abstractNote={BACKGROUND Salmon poisoning disease (SPD) is a trematode-borne disease of dogs caused by Neorickettsia helminthoeca. OBJECTIVES To determine risk factors and spatial epidemiology of SPD in dogs from northern California; to describe the clinicopathologic, microbiologic, and imaging findings of SPD in these dogs; and to evaluate treatments and outcomes for SPD. ANIMALS Twenty-nine dogs with SPD based on the finding of trematode ova in the feces, or organisms consistent with N. helminthoeca in specimens submitted for microscopic examination. METHODS Information regarding signalment, fish exposure, clinical signs, diagnostic evaluation, treatments, and outcomes was obtained for each dog. Archived lymph node aspirates and histopathology specimens were subjected to polymerase chain reaction (PCR) testing for Neorickettsia spp. RESULTS Labrador Retrievers and intact male dogs were overrepresented. Exposure locations were often distant from the dogs' residence. Some dogs had neurologic signs, including twitching and seizures. Dogs lacking peripheral lymphadenomegaly had abdominal lymphadenomegaly on ultrasound examination. A combination of centrifugation fecal flotation and sedimentation had greatest sensitivity for finding fluke ova. N. helminthoeca DNA was amplified by PCR from 4/10 dogs. Penicillins, cephalosporins, and chloramphenicol did not appear to be effective treatments. Mortality rate was 4/29 (14%). CONCLUSIONS AND CLINICAL IMPORTANCE SPD should be suspected in dogs with inappetence, gastrointestinal, or neurologic signs, with or without fever or peripheral lymphadenomegaly in the appropriate geographical setting. Diagnosis is facilitated by a combination of fecal sedimentation and centrifugal flotation, abdominal ultrasonography, and PCR-based assays on lymphoid tissue. The treatment of choice is tetracycline antimicrobials.}, number={3}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Sykes, J.E. and Marks, S.L. and Mapes, S. and Schultz, R.M. and Pollard, R.E. and Tokarz, D. and Pesavento, P.P. and Lindsay, L.L. and Foley, J.E.}, year={2010}, month={Mar}, pages={504–513} } @article{rainier_bui_mark_thomas_tokarz_ming_delaney_richardson_albers_matsunami_et al._2008, title={Neuropathy Target Esterase Gene Mutations Cause Motor Neuron Disease}, volume={82}, ISSN={0002-9297}, url={http://dx.doi.org/10.1016/j.ajhg.2007.12.018}, DOI={10.1016/j.ajhg.2007.12.018}, abstractNote={The possibility that organophosphorus (OP) compounds contribute to motor neuron disease (MND) is supported by association of paraoxonase 1 polymorphisms with amyotrophic lateral sclerosis (ALS) and the occurrence of MND in OP compound-induced delayed neuropathy (OPIDN), in which neuropathy target esterase (NTE) is inhibited by organophosphorylation. We evaluated a consanguineous kindred and a genetically unrelated nonconsanguineous kindred in which affected subjects exhibited progressive spastic paraplegia and distal muscle wasting. Affected subjects resembled those with OPIDN and those with Troyer Syndrome due to SPG20/spartin gene mutation (excluded by genetic linkage and SPG20/spartin sequence analysis). Genome-wide analysis suggested linkage to a 22 cM homozygous locus (D19S565 to D19S884, maximum multipoint LOD score 3.28) on chromosome 19p13 to which NTE had been mapped (GenBank AJ004832). NTE was a candidate because of its role in OPIDN and the similarity of our patients to those with OPIDN. Affected subjects in the consanguineous kindred were homozygous for disease-specific NTE mutation c.3034A-->G that disrupted an interspecies conserved residue (M1012V) in NTE's catalytic domain. Affected subjects in the nonconsanguineous family were compound heterozygotes: one allele had c.2669G-->A mutation, which disrupts an interspecies conserved residue in NTE's catalytic domain (R890H), and the other allele had an insertion (c.2946_2947insCAGC) causing frameshift and protein truncation (p.S982fs1019). Disease-specific, nonconserved NTE mutations in unrelated MND patients indicates NTE's importance in maintaining axonal integrity, raises the possibility that NTE pathway disturbances contribute to other MNDs including ALS, and supports the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds.}, number={3}, journal={The American Journal of Human Genetics}, publisher={Elsevier BV}, author={Rainier, Shirley and Bui, Melanie and Mark, Erin and Thomas, Donald and Tokarz, Debra and Ming, Lei and Delaney, Colin and Richardson, Rudy J. and Albers, James W. and Matsunami, Nori and et al.}, year={2008}, month={Mar}, pages={780–785} } @article{schrenzel_maalouf_gaffney_tokarz_keener_mcclure_griffey_mcaloose_rideout_2005, title={Molecular characterization of isosporoid coccidia (Isospora and Atoxoplasma spp.) in passerine birds.}, volume={91}, ISSN={0022-3395 1937-2345}, url={http://dx.doi.org/10.1645/ge-3310}, DOI={10.1645/ge-3310}, abstractNote={Prevalence and disease caused by isosporoid coccidia in passerine birds are well recognized, but confusion about the life cycles of the parasites has led to taxonomic inconsistencies. In this study, we characterized segments of the chromosomal small and large-subunit ribosomal RNA (rRNA) genes of coccidial parasites from 23 species of passerine birds, as well as heat shock protein 70, apicoplast rRNA, and chromosomal 5.8s rRNA genes from a subgroup of these animals, and we correlated genetic data with morphologic findings for different parasite developmental stages, host phylogeny, and overall taxonomic relations within the phylum Apicomplexa. Our findings indicate that isosporoid coccidia of passerine birds are monophyletic but exhibit substantial diversity, with most avian species having one or several unique parasite lineages that underwent synchronous speciation with their hosts, interrupted by sporadic episodes of lateral transmission across species and families. Molecular analyses support a homoxenous life cycle, with sexual forms occurring chiefly in the intestines and asexual merozoites present systemically. Rarely, extraintestinal sexual stages can occur. The passerine coccidia are genetically most closely related to species of Eimeria rather than Isospora. We suggest that these parasites, whether identified from blood merozoite stages or fecal oocysts, be provisionally grouped as a homogeneous clade of individual species in a single taxon and formally named when reliable criteria allowing reclassification of related genera in the suborder Eimeriina are clarified.}, number={3}, journal={Journal of Parasitology}, publisher={American Society of Parasitologists}, author={Schrenzel, Mark D. and Maalouf, Gabriel A. and Gaffney, Patricia M. and Tokarz, Debra and Keener, Laura L. and McClure, Diane and Griffey, Stephen and McAloose, D. and Rideout, Bruce A.}, year={2005}, month={Jun}, pages={635–647} } @article{rainier_thomas_tokarz_ming_bui_plein_zhao_lemons_albin_delaney_et al._2004, title={Myofibrillogenesis Regulator 1 Gene Mutations Cause Paroxysmal Dystonic Choreoathetosis}, volume={61}, ISSN={0003-9942}, url={http://dx.doi.org/10.1001/archneur.61.7.1025}, DOI={10.1001/archneur.61.7.1025}, abstractNote={BACKGROUND Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary movements that occur spontaneously while at rest and following caffeine or alcohol consumption. Previously, we and others identified a locus for autosomal dominant PDC on chromosome 2q33-2q35. OBJECTIVE To identify the PDC gene. DESIGN Analysis of PDC positional candidate genes by exon sequencing and reverse transcription-polymerase chain reaction. SETTING Outpatient clinical and molecular genetic laboratory at a university hospital. Patients Affected (n = 12) and unaffected (n = 26) subjects from 2 unrelated families with PDC and 105 unrelated control subjects. RESULTS We identified missense mutations in the myofibrillogenesis regulator gene (MR-1) in affected subjects in 2 unrelated PDC kindreds. These mutations were absent in control subjects and caused substitutions of valine for alanine at amino acid positions 7 and 9. The substitutions disturb interspecies conserved residues and are predicted to alter the MR-1 gene's amino-terminal alpha helix. The MR-1 exon containing these mutations (exon 1) was expressed only in the brain, a finding that explains the brain-specific symptoms of subjects with these mutations. CONCLUSIONS Although MR-1 gene function is unknown, the precedence of ion channel disturbance in other episodic neurologic disorders suggests that the pathophysiologic features of PDC also involve abnormal ion localization. The discovery that MR-1 mutations underlie PDC provides opportunities to explore this condition's pathophysiologic characteristics and may provide insight into the causes of other paroxysmal neurologic disorders as well as the neurophysiologic mechanisms of alcohol and caffeine, which frequently precipitate PDC attacks.}, number={7}, journal={Archives of Neurology}, publisher={American Medical Association (AMA)}, author={Rainier, S. and Thomas, D. and Tokarz, D. and Ming, L. and Bui, M. and Plein, E. and Zhao, X. and Lemons, R. and Albin, R. and Delaney, C. and et al.}, year={2004}, month={Jul}, pages={1025–1029} } @article{rainier_chai_tokarz_nicholls_fink_2003, title={NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia (SPG6)}, volume={73}, ISSN={0002-9297}, url={http://dx.doi.org/10.1086/378817}, DOI={10.1086/378817}, abstractNote={The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders characterized by progressive lower-extremity weakness and spasticity. The molecular pathogenesis is poorly understood. We report discovery of a dominant negative mutation in the NIPA1 gene in a kindred with autosomal dominant HSP (ADHSP), linked to chromosome 15q11-q13 (SPG6 locus); and precisely the same mutation in an unrelated kindred with ADHSP that was too small for meaningful linkage analysis. NIPA1 is highly expressed in neuronal tissues and encodes a putative membrane transporter or receptor. Identification of the NIPA1 function and ligand will aid an understanding of axonal neurodegeneration in HSP and may have important therapeutic implications.}, number={4}, journal={The American Journal of Human Genetics}, publisher={Elsevier BV}, author={Rainier, Shirley and Chai, Jing-Hua and Tokarz, Debra and Nicholls, Robert D. and Fink, John K.}, year={2003}, month={Oct}, pages={967–971} }