13 results on '"Ezzell, J Ashley"'
Search Results
2. Tumor Necrosis Factor Alpha-Induced Interleukin-1 Alpha Synthesis and Cell Death Is Increased in Mouse Epithelial Cells Infected With Chlamydia muridarum.
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Nagarajan, Uma M, Cho, Crescentia, Gyorke, Clare E, Nagarajan, Shanmugam, Ezzell, J Ashley, Brochu, Hayden, Huntress, Ian, Harrell, Erin, and Peng, Xinxia
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TUMOR necrosis factors ,EPITHELIAL cells ,CELL death ,CHLAMYDIA infections ,CHLAMYDIA ,RESEARCH ,ANIMAL experimentation ,RESEARCH methodology ,INTERLEUKIN-1 ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,MICE - Abstract
Chlamydia trachomatis-genital infection in women can be modeled in mice using Chlamydia muridarum. Using this model, it has been shown that the cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1α lead to irreversible tissue damage in the oviducts. In this study, we investigated the contribution of TNFα on IL-1α synthesis in infected epithelial cells. We show that C muridarum infection enhanced TNFα-induced IL-1α expression and release in a mouse epithelial cell line. In addition to IL-1α, several TNFα-induced inflammatory genes were also highly induced, and infection enhanced TNF-induced cell death. In the mouse model of genital infection, oviducts from mice lacking the TNFα receptor displayed minimal staining for IL-1α compared with wild-type oviducts. Our results suggest TNFα and IL-1α enhance each other's downstream effects resulting in a hyperinflammatory response to chlamydial infection. We propose that biologics targeting TNF-induced IL-1α synthesis could be used to mitigate tissue damage during chlamydial infection. [ABSTRACT FROM AUTHOR]
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- 2021
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3. Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat.
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Pelot, Nicole A., Goldhagen, Gabriel B., Cariello, Jake E., Musselman, Eric D., Clissold, Kara A., Ezzell, J. Ashley, and Grill, Warren M.
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VAGUS nerve ,ELECTRIC stimulation ,NEURAL stimulation ,MORPHOLOGY ,TREATMENT effectiveness - Abstract
It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles—and the fascicles were smaller—than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS. [ABSTRACT FROM AUTHOR]
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- 2020
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4. Functional vagotopy in the cervical vagus nerve of the domestic pig: implications for the study of vagus nerve stimulation.
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Settell, Megan L, Pelot, Nicole A, Knudsen, Bruce E, Dingle, Aaron M, McConico, Andrea L, Nicolai, Evan N, Trevathan, James K, Ezzell, J Ashley, Ross, Erika K, Gustafson, Kenneth J, Shoffstall, Andrew J, Williams, Justin C, Zeng, Weifeng, Poore, Samuel O, Populin, Luis C, Suminski, Aaron J, Grill, Warren M, and Ludwig, Kip A
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- 2020
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5. Corrigendum: Functional vagotopy in the cervical vagus nerve of the domestic pig: implications for the study of vagus nerve stimulation (2020 J. Neural Eng.17 026022).
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Settell, Megan L, Pelot, Nicole A, Knudsen, Bruce E, Dingle, Aaron M, McConico, Andrea L, Nicolai, Evan N, Trevathan, James K, Ezzell, J Ashley, Ross, Erika K, Gustafson, Kenneth J, Shoffstall, Andrew J, Williams, Justin C, Zeng, Weifeng, Poore, Samuel O, Populin, Luis C, Suminski, Aaron J, Grill, Warren M, and Ludwig, Kip A
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- 2021
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6. IL-1a Is Essential for Oviduct Pathology during Genital Chlamydial Infection in Mice.
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Gyorke, Clare E., Kollipara, Avinash, Allen, John, Yugen Zhang, Ezzell, J. Ashley, Darville, Toni, Montgomery, Stephanie A., and Nagarajan, Uma M.
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CHLAMYDIA infections , *OVIDUCT , *GENITALIA infections , *FALLOPIAN tubes , *CHLAMYDIA trachomatis - Abstract
Chlamydia trachomatis infection of the female genital tract can lead to irreversible fallopian tube scarring. In the mouse model of genital infection using Chlamydia muridarum, IL-1R signaling plays a critical role in oviduct tissue damage. In this study, we investigated the pathologic role of IL-1a, one of the two proinflammatory cytokines that bind to IL-1R. Il1a2/2 mice infected with C. muridarum cleared infection at their cervix at the same rate as wild-type (WT) mice, but were significantly protected from end point oviduct damage and fibrosis. The contribution of IL-1a to oviduct pathology was more dramatic than observed in mice deficient for IL-1b. Although chlamydial burden was similar in WT and Il1a2/2 oviduct during peak days of infection, levels of IL-1b, IL-6, CSF3, and CXCL2 were reduced in Il1a2/2 oviduct lysates. During infection, Il1a2/2 oviducts and uterine horns exhibited reduced neutrophil infiltration, and this reduction persisted after the infection resolved. The absence of IL-1a did not compromise CD4 T cell recruitment or function during primary or secondary chlamydial infection. IL-1a is expressed predominantly by luminal cells of the genital tract in response to infection, and low levels of expression persisted after the infection cleared. Ab-mediated depletion of IL-1a in WT mice prevented infection-induced oviduct damage, further supporting a key role for IL-1a in oviduct pathology. [ABSTRACT FROM AUTHOR]
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- 2020
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7. TDP-43 pathology links innate and adaptive immunity in amyotrophic lateral sclerosis.
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Evangelista BA, Ragusa JV, Pellegrino K, Wu Y, Quiroga-Barber IY, Cahalan SR, Arooji OK, Madren JA, Schroeter S, Cozzarin J, Xie L, Chen X, White KK, Ezzell JA, Iannone MA, Cohen S, Traub RE, Li X, Bedlack R, Phanstiel DH, Meeker R, Stanley N, and Cohen TJ
- Abstract
Amyotrophic lateral sclerosis is the most common fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, Transactive Response DNA Binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 pathology elicits disease-modifying immune responses in ALS remains underexplored. In this study, we demonstrate that TDP-43 pathology is internalized by antigen presenting cells, causes vesicle rupture, and leads to innate and adaptive immune cell activation. Using a multiplex imaging platform, we observed interactions between innate and adaptive immune cells near TDP-43 pathological lesions in ALS brain. We used a mass cytometry-based whole-blood stimulation assay to provide evidence that ALS patient peripheral immune cells exhibit responses to TDP-43 aggregates. Taken together, this study provides a novel link between TDP-43 pathology and ALS immune dysfunction, and further highlights the translational and diagnostic implications of monitoring and manipulating the ALS immune response.
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- 2024
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8. RNA-binding deficient TDP-43 drives cognitive decline in a mouse model of TDP-43 proteinopathy.
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Necarsulmer JC, Simon JM, Evangelista BA, Chen Y, Tian X, Nafees S, Marquez AB, Jiang H, Wang P, Ajit D, Nikolova VD, Harper KM, Ezzell JA, Lin FC, Beltran AS, Moy SS, and Cohen TJ
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- Humans, Animals, Mice, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Disease Models, Animal, RNA, TDP-43 Proteinopathies genetics, TDP-43 Proteinopathies metabolism, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration metabolism, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Cognitive Dysfunction
- Abstract
TDP-43 proteinopathies including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic acid-binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed endogenous models of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of acetylation-mimic TDP-43
K145Q resulted in stress-induced nuclear TDP-43 foci and loss of TDP-43 function in primary mouse and human-induced pluripotent stem cell (hiPSC)-derived cortical neurons. Mice harboring the TDP-43K145Q mutation recapitulated key hallmarks of FTLD, including progressive TDP-43 phosphorylation and insolubility, TDP-43 mis-localization, transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which TDP-43 acetylation drives neuronal dysfunction and cognitive decline through aberrant splicing and transcription of critical genes that regulate synaptic plasticity and stress response signaling. The neurodegenerative cascade initiated by TDP-43 acetylation recapitulates many aspects of human FTLD and provides a new paradigm to further interrogate TDP-43 proteinopathies., Competing Interests: JN, JS, BE, YC, XT, SN, AM, HJ, PW, DA, VN, KH, JE, FL, AB, SM, TC No competing interests declared, (© 2023, Necarsulmer et al.)- Published
- 2023
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9. Intermediate filament dysregulation in astrocytes in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN).
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Battaglia R, Faridounnia M, Beltran A, Robinson J, Kinghorn K, Ezzell JA, Bharucha-Goebel D, Bonnemann C, Hooper JE, Opal P, Bouldin TW, Armao D, and Snider N
- Abstract
Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, which regulates intermediate filament (IF) turnover. Previous neuropathological studies and examination of postmortem brain tissue in the current study revealed involvement of astrocytes in GAN. To develop a clinically-relevant model, we reprogrammed skin fibroblasts from seven GAN patients to pluripotent stem cells (iPSCs), which were used to generate neural progenitor cells (NPCs), astrocytes, and brain organoids. Multiple isogenic control clones were derived via CRISPR/Cas9 gene editing of one patient line carrying the G332R gigaxonin mutation. All GAN iPSCs were deficient for gigaxonin and displayed patient-specific increased vimentin expression. GAN NPCs had lower nestin expression and fewer nestin-positive cells compared to isogenic controls, but nestin morphology was unaffected. GAN brain organoids were marked by the presence of neurofilament and GFAP aggregates. GAN iPSC-astrocytes displayed striking dense perinuclear vimentin and GFAP accumulations and abnormal nuclear morphology. In over-expression systems, GFAP oligomerization and perinuclear aggregation were augmented in the presence of vimentin. GAN patient cells with large perinuclear vimentin aggregates accumulated significantly more nuclear KLHL16 mRNA compared to cells without vimentin aggregates. As an early effector of KLHL16 mutations, vimentin may be a potential target in GAN.
- Published
- 2023
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10. Combination of Polymeric Micelle Formulation of TGFβ Receptor Inhibitors and Paclitaxel Produce Consistent Response Across Different Mouse Models of TNBC.
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Vinod N, Hwang D, Fussell SC, Owens TC, Tofade OC, Copling S, Ramsey JD, Rädler PD, Atkins HM, Livingston EE, Ezzell JA, Sokolsky-Papkov M, Yuan H, Perou CM, and Kabanov AV
- Abstract
Triple-negative breast cancer (TNBC) is notoriously difficult to treat due to the lack of targetable receptors and sometimes poor response to chemotherapy. The transforming growth factor-beta (TGFβ) family of proteins and their receptors (TGFR) are highly expressed in TNBC and implicated in chemotherapy-induced cancer stemness. Here we evaluated combination treatments using experimental TGFR inhibitors (TGFβi), SB525334 (SB), and LY2109761 (LY) with Paclitaxel (PTX) chemotherapy. These TGFβi target TGFR-I (SB) or both TGFR-I&II (LY). Due to the poor water solubility of these drugs, we incorporated each of them in poly(2-oxazoline) (POx) high-capacity polymeric micelles (SB-POx and LY-POx). We assessed their anti-cancer effect as single agents and in combination with micellar Paclitaxel (PTX-POx) using multiple immunocompetent TNBC mouse models that mimic human subtypes (4T1, T11-Apobec and T11-UV). While either TGFβi or PTX showed a differential effect in each model as single agents, the combinations were consistently effective against all three models. Genetic profiling of the tumors revealed differences in the expression levels of genes associated with TGFβ, EMT, TLR-4, and Bcl2 signaling, alluding to the susceptibility to specific gene signatures to the treatment. Taken together, our study suggests that TGFβi and PTX combination therapy using high-capacity POx micelle delivery provides a robust anti-tumor response in multiple TNBC subtype mouse models., Competing Interests: Conflict of Interest: A.V.K. is an inventor on patents pertinent to the subject matter of the present contribution, co-founder, stockholder and director of DelAqua Pharmaceuticals Inc. having intent of commercial development of POx-based drug formulations. A.V.K. is also a co-founder, stockholder and director of SoftKemo Pharma Corp. and BendaRx Pharma Corp., which develop polymeric drug formulation and a blood cancer drug. M.S.P. discloses potential interest in DelAqua Pharmaceuticals Inc., SoftKemo Pharma Corp. and BendaRx Pharma Corp. as a spouse of a co-founder. C.M.P is an equity stockholder and consultant of BioClassifier LLC; C.M.P is also listed as an inventor on patent applications for the Breast PAM50 Subtyping assay.
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- 2023
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11. Intermediate filament dysregulation and astrocytopathy in the human disease model of KLHL16 mutation in giant axonal neuropathy (GAN).
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Battaglia R, Faridounnia M, Beltran A, Robinson J, Kinghorn K, Ezzell JA, Bharucha-Goebel D, Bonnemann C, Hooper JE, Opal P, Bouldin TW, Armao D, and Snider N
- Abstract
Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, a regulator of intermediate filament (IF) protein turnover. Previous neuropathological studies and our own examination of postmortem GAN brain tissue in the current study revealed astrocyte involvement in GAN. To study the underlying mechanisms, we reprogrammed skin fibroblasts from seven GAN patients carrying different KLHL16 mutations to iPSCs. Isogenic controls with restored IF phenotypes were derived via CRISPR/Cas9 editing of one patient carrying a homozygous missense mutation (G332R). Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxonin, which was restored in the isogenic control. GAN iPSCs displayed patient-specific increased vimentin expression, while GAN NPCs had decreased nestin expression compared to isogenic control. The most striking phenotypes were observed in GAN iPSC-astrocytes and brain organoids, which exhibited dense perinuclear IF accumulations and abnormal nuclear morphology. GAN patient cells with large perinuclear vimentin aggregates accumulated nuclear KLHL16 mRNA. In over-expression studies, GFAP oligomerization and perinuclear aggregation were potentiated in the presence of vimentin. As an early effector of KLHL16 mutations, vimentin may serve as a potential therapeutic target in GAN.
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- 2023
- Full Text
- View/download PDF
12. Corrigendum: Functional vagotopy in the cervical vagus nerve of the domestic pig: implications for the study of vagus nerve stimulation (2020 J. Neural Eng. 17 026022).
- Author
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Settell ML, Pelot NA, Knudsen BE, Dingle AM, McConico AL, Nicolai EN, Trevathan JK, Ezzell JA, Ross EK, Gustafson KJ, Shoffstall AJ, Williams JC, Zeng W, Poore SO, Populin LC, Suminski AJ, Grill WM, and Ludwig KA
- Published
- 2021
- Full Text
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13. cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer.
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Cozzo AJ, Sundaram S, Zattra O, Qin Y, Freemerman AJ, Essaid L, Darr DB, Montgomery SA, McNaughton KK, Ezzell JA, Galanko JA, Troester MA, and Makowski L
- Abstract
Unlabelled: Epidemiologic studies have associated obesity with increased risk of the aggressive basal-like breast cancer (BBC) subtype. Hepatocyte growth factor (HGF) signaling through its receptor, cMET, is elevated in obesity and is a pro-tumorigenic pathway strongly associated with BBC. We previously reported that high fat diet (HFD) elevated HGF, cMET, and phospho-cMET in normal mammary gland, with accelerated tumor development, compared to low fat diet (LFD)-fed lean controls in a murine model of BBC. We also showed that weight loss resulted in a significant reversal of HFD-induced effects on latency and elevation of HGF/cMET signaling in normal mammary and cMET in normal mammary and tumors. Here, we sought to inhibit BBC tumor progression in LFD- and HFD-fed C3(1)-Tag BBC mice using a small molecule cMET inhibitor, and began crizotinib treatment (50 mg/kg body weight by oral gavage) upon identification of the first palpable tumor. We next investigated if administering crizotinib in a window prior to tumor development would inhibit or delay BBC tumorigenesis., Treatment: Crizotinib significantly reduced mean tumor burden by 27.96 and 37.29 %, and mean tumor vascularity by 35.04 and 33.52 %, in our LFD- and HFD-fed C3(1)-Tag BBC mice, respectively., Prevention: Crizotinib significantly accelerated primary tumor progression in both diet groups but had no effect on total tumor progression or total tumor burden. In sum, cMET inhibition by crizotinib limited tumor development and microvascular density in basal-like tumor-bearing mice but did not appear to be an effective preventive agent for BBC.
- Published
- 2016
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