143 results on '"J. Will Thompson"'
Search Results
2. Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis
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Charles D. Giamberardino, Wiley A. Schell, Jennifer L. Tenor, Dena L. Toffaletti, Julia R. Palmucci, Choiselle Marius, Jane-Valeriane K. Boua, Quinlyn Soltow, Robert Mansbach, M. Arthur Moseley, J. Will Thompson, Laura G. Dubois, William Hope, John R. Perfect, and Karen Joy Shaw
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Cryptococcus ,APX2039 ,APX001 ,fosmanogepix ,manogepix ,Gwt1 ,Microbiology ,QR1-502 - Abstract
ABSTRACT Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficacy of APX2039 in mouse and rabbit models of CM. In the mouse model, the controls had a mean lung fungal burden of 5.95 log10 CFU/g, whereas those in the fluconazole-, amphotericin B-, and APX2039-treated mice were 3.56, 4.59, and 1.50 log10 CFU/g, respectively. In the brain, the control mean fungal burden was 7.97 log10 CFU/g, while the burdens were 4.64, 7.16, and 1.44 log10 CFU/g for treatment with fluconazole, amphotericin B, and APX2039, respectively. In the rabbit model of CM, the oral administration of APX2039 at 50 mg/kg of body weight twice a day (BID) resulted in a rapid decrease in the cerebrospinal fluid (CSF) fungal burden, and the burden was below the limit of detection by day 10 postinfection. The effective fungicidal activity (EFA) was −0.66 log10 CFU/mL/day, decreasing from an average of 4.75 log10 CFU/mL to 0 CFU/mL, over 8 days of therapy, comparing favorably with good clinical outcomes in humans associated with reductions of the CSF fungal burden of −0.4 log10 CFU/mL/day, and, remarkably, 2-fold the EFA of amphotericin B deoxycholate in this model (−0.33 log10 CFU/mL/day). A total drug exposure of the area under the concentration-time curve from 0 to 24 h (AUC0–24) of 25 to 50 mg · h/L of APX2039 resulted in near-maximal antifungal activity. These data support the further preclinical and clinical evaluation of APX2039 as a new oral fungicidal monotherapy for the treatment of CM. IMPORTANCE Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. Here, we demonstrated the efficacy of APX2039, the second member of the gepix class, in rabbit and mouse models of cryptococcal meningitis. We also analyzed the drug levels in the blood and cerebrospinal fluid in the highly predictive rabbit model and built a mathematical model to describe the behavior of the drug with respect to the elimination of the fungal pathogen. We demonstrated that the oral administration of APX2039 resulted in a rapid decrease in the CSF fungal burden, with an effective fungicidal activity of −0.66 log10 CFU/mL/day, comparing favorably with good clinical outcomes in humans associated with reductions of −0.4 log10 CFU/mL/day. The drug APX2039 had good penetration of the central nervous system and is an excellent candidate for future clinical testing in humans for the treatment of CM.
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- 2022
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3. A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure
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Raymond J. Langley, Marie E. Migaud, Lori Flores, J. Will Thompson, Elizabeth A. Kean, Murphy M. Mostellar, Matthew Mowry, Patrick Luckett, Lina D. Purcell, James Lovato, Sheetal Gandotra, Ryan Benton, D. Clark Files, Kevin S. Harrod, Mark N. Gillespie, and Peter E. Morris
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Medicine ,Science - Abstract
Abstract Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.
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- 2021
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4. Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression
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Siamak MahmoudianDehkordi, Ahmed T. Ahmed, Sudeepa Bhattacharyya, Xianlin Han, Rebecca A. Baillie, Matthias Arnold, Michelle K. Skime, Lisa St. John-Williams, M. Arthur Moseley, J. Will Thompson, Gregory Louie, Patricio Riva-Posse, W. Edward Craighead, William McDonald, Ranga Krishnan, A. John Rush, Mark A. Frye, Boadie W. Dunlop, Richard M. Weinshilboum, Rima Kaddurah-Daouk, and The Mood Disorders Precision Medicine Consortium (MDPMC)
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines—including arginine, proline, and methionine sulfoxide—were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (
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- 2021
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5. Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome
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Matthias Arnold, Kwangsik Nho, Alexandra Kueider-Paisley, Tyler Massaro, Kevin Huynh, Barbara Brauner, Siamak MahmoudianDehkordi, Gregory Louie, M. Arthur Moseley, J. Will Thompson, Lisa St John-Williams, Jessica D. Tenenbaum, Colette Blach, Rui Chang, Roberta D. Brinton, Rebecca Baillie, Xianlin Han, John Q. Trojanowski, Leslie M. Shaw, Ralph Martins, Michael W. Weiner, Eugenia Trushina, Jon B. Toledo, Peter J. Meikle, David A. Bennett, Jan Krumsiek, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, and Gabi Kastenmüller
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Science - Abstract
Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.
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- 2020
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6. Influence of Sex on Platelet Reactivity in Response to Aspirin
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Kevin A. Friede, Margaret M. Infeld, Ru San Tan, Holly J. Knickerbocker, Rachel A. Myers, Laura G. Dubois, J. Will Thompson, Rima Kaddurah‐Daouk, Geoffrey S. Ginsburg, Thomas L. Ortel, and Deepak Voora
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aspirin ,platelets ,sex differences ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background There are sex differences in the efficacy and safety of aspirin for the prevention of myocardial infarction and stroke. Whether this is explained by underlying differences in platelet reactivity and aspirin response remains poorly understood. Methods and Results Healthy volunteers (n=378 208 women) and patients with coronary artery disease or coronary artery disease risk factors (n=217 112 women) took aspirin for 4 weeks. Light transmittance aggregometry using platelet‐rich plasma was used to measure platelet reactivity in response to epinephrine, collagen, and ADP at baseline, 3 hours after the first aspirin dose, and after 4 weeks of daily aspirin therapy. A subset of patients underwent pharmacokinetic and pharmacodynamic assessment with levels of salicylate and cyclooxygenase‐1–derived prostaglandin metabolites and light transmittance aggregometry in response to arachidonic acid and after ex vivo exposure to aspirin. At baseline, women had increased platelet aggregation in response to ADP and collagen. Innate platelet response to aspirin, assessed with ex vivo aspirin exposure of baseline platelets, did not differ by sex. Three hours after the first oral aspirin dose, platelet aggregation was inhibited in women to a greater degree in response to epinephrine and to a lesser degree with collagen. After 4 weeks of daily therapy, despite higher salicylate concentrations and greater cyclooxygenase‐1 inhibition, women exhibited an attenuation of platelet inhibition in response to epinephrine and ADP. Conclusions We observed agonist‐dependent sex differences in platelet responses to aspirin. Despite higher cyclooxygenase‐1 inhibition, daily aspirin exposure resulted in a paradoxical attenuation of platelet inhibition in response to epinephrine and ADP over time in women but not in men.
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- 2020
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7. CoA synthase regulates mitotic fidelity via CBP-mediated acetylation
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Chao-Chieh Lin, Mayumi Kitagawa, Xiaohu Tang, Ming-Hsin Hou, Jianli Wu, Dan Chen Qu, Vinayaka Srinivas, Xiaojing Liu, J. Will Thompson, Bernard Mathey-Prevot, Tso-Pang Yao, Sang Hyun Lee, and Jen-Tsan Chi
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Science - Abstract
The temporal activation of kinases and timely ubiquitin-mediated degradation is central to faithful mitosis. Here the authors show that acetylation controlled by Coenzyme A synthase (COASY) and acetyltransferase CBP constitutes a mechanism that ensures faithful mitosis.
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- 2018
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8. Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950–Metabolites in Frozen Human Plasma[S]
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John A. Bowden, Alan Heckert, Candice Z. Ulmer, Christina M. Jones, Jeremy P. Koelmel, Laila Abdullah, Linda Ahonen, Yazen Alnouti, Aaron M. Armando, John M. Asara, Takeshi Bamba, John R. Barr, Jonas Bergquist, Christoph H. Borchers, Joost Brandsma, Susanne B. Breitkopf, Tomas Cajka, Amaury Cazenave-Gassiot, Antonio Checa, Michelle A. Cinel, Romain A. Colas, Serge Cremers, Edward A. Dennis, James E. Evans, Alexander Fauland, Oliver Fiehn, Michael S. Gardner, Timothy J. Garrett, Katherine H. Gotlinger, Jun Han, Yingying Huang, Aveline Huipeng Neo, Tuulia Hyötyläinen, Yoshihiro Izumi, Hongfeng Jiang, Houli Jiang, Jiang Jiang, Maureen Kachman, Reiko Kiyonami, Kristaps Klavins, Christian Klose, Harald C. Köfeler, Johan Kolmert, Therese Koal, Grielof Koster, Zsuzsanna Kuklenyik, Irwin J. Kurland, Michael Leadley, Karen Lin, Krishna Rao Maddipati, Danielle McDougall, Peter J. Meikle, Natalie A. Mellett, Cian Monnin, M. Arthur Moseley, Renu Nandakumar, Matej Oresic, Rainey Patterson, David Peake, Jason S. Pierce, Martin Post, Anthony D. Postle, Rebecca Pugh, Yunping Qiu, Oswald Quehenberger, Parsram Ramrup, Jon Rees, Barbara Rembiesa, Denis Reynaud, Mary R. Roth, Susanne Sales, Kai Schuhmann, Michal Laniado Schwartzman, Charles N. Serhan, Andrej Shevchenko, Stephen E. Somerville, Lisa St. John-Williams, Michal A. Surma, Hiroaki Takeda, Rhishikesh Thakare, J. Will Thompson, Federico Torta, Alexander Triebl, Martin Trötzmüller, S. J. Kumari Ubhayasekera, Dajana Vuckovic, Jacquelyn M. Weir, Ruth Welti, Markus R. Wenk, Craig E. Wheelock, Libin Yao, Min Yuan, Xueqing Heather Zhao, and Senlin Zhou
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fatty acyls ,glycerolipids ,lipids ,phospholipids ,quality control ,quantitation ,Biochemistry ,QD415-436 - Abstract
As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950–Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.
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- 2017
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9. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells
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Amy E. Baek, Yen-Rei A. Yu, Sisi He, Suzanne E. Wardell, Ching-Yi Chang, Sanghoon Kwon, Ruchita V. Pillai, Hannah B. McDowell, J. Will Thompson, Laura G. Dubois, Patrick M. Sullivan, Jongsook K. Kemper, Michael D. Gunn, Donald P. McDonnell, and Erik R. Nelson
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Science - Abstract
High cholesterol is a risk factor for breast cancer recurrence. Here the authors show that cholesterol promotes breast cancer metastasis via its metabolite 27-hydroxycholesterol (27HC) that acts on immune myeloid cells residing at the distal metastatic sites, thus promoting an immune suppressive environment.
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- 2017
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10. Nasopharyngeal Protein Biomarkers of Acute Respiratory Virus Infection
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Thomas W. Burke, Ricardo Henao, Erik Soderblom, Ephraim L. Tsalik, J. Will Thompson, Micah T. McClain, Marshall Nichols, Bradly P. Nicholson, Timothy Veldman, Joseph E. Lucas, M. Arthur Moseley, Ronald B. Turner, Robert Lambkin-Williams, Alfred O. Hero, III, Christopher W. Woods, and Geoffrey S. Ginsburg
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Infectious disease ,Influenza ,Human rhinovirus ,Proteomics ,Diagnostic biomarker ,Medicine ,Medicine (General) ,R5-920 - Abstract
Infection of respiratory mucosa with viral pathogens triggers complex immunologic events in the affected host. We sought to characterize this response through proteomic analysis of nasopharyngeal lavage in human subjects experimentally challenged with influenza A/H3N2 or human rhinovirus, and to develop targeted assays measuring peptides involved in this host response allowing classification of acute respiratory virus infection. Unbiased proteomic discovery analysis identified 3285 peptides corresponding to 438 unique proteins, and revealed that infection with H3N2 induces significant alterations in protein expression. These include proteins involved in acute inflammatory response, innate immune response, and the complement cascade. These data provide insights into the nature of the biological response to viral infection of the upper respiratory tract, and the proteins that are dysregulated by viral infection form the basis of signature that accurately classifies the infected state. Verification of this signature using targeted mass spectrometry in independent cohorts of subjects challenged with influenza or rhinovirus demonstrates that it performs with high accuracy (0.8623 AUROC, 75% TPR, 97.46% TNR). With further development as a clinical diagnostic, this signature may have utility in rapid screening for emerging infections, avoidance of inappropriate antibacterial therapy, and more rapid implementation of appropriate therapeutic and public health strategies.
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- 2017
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11. Pathogen Evasion of Chemokine Response Through Suppression of CXCL10
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Alejandro L. Antonia, Kyle D. Gibbs, Esme D. Trahair, Kelly J. Pittman, Amelia T. Martin, Benjamin H. Schott, Jeffrey S. Smith, Sudarshan Rajagopal, J. Will Thompson, Richard Lee Reinhardt, and Dennis C. Ko
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CXCL10 ,CXCR3 ,Leishmania ,gp63 ,leishmanolysin ,Chlamydia ,Microbiology ,QR1-502 - Abstract
Clearance of intracellular pathogens, such as Leishmania (L.) major, depends on an immune response with well-regulated cytokine signaling. Here we describe a pathogen-mediated mechanism of evading CXCL10, a chemokine with diverse antimicrobial functions, including T cell recruitment. Infection with L. major in a human monocyte cell line induced robust CXCL10 transcription without increasing extracellular CXCL10 protein concentrations. We found that this transcriptionally independent suppression of CXCL10 is mediated by the virulence factor and protease, glycoprotein-63 (gp63). Specifically, GP63 cleaves CXCL10 after amino acid A81 at the base of a C-terminal alpha-helix. Cytokine cleavage by GP63 demonstrated specificity, as GP63 cleaved CXCL10 and its homologs, which all bind the CXCR3 receptor, but not distantly related chemokines, such as CXCL8 and CCL22. Further characterization demonstrated that CXCL10 cleavage activity by GP63 was produced by both extracellular promastigotes and intracellular amastigotes. Crucially, CXCL10 cleavage impaired T cell chemotaxis in vitro, indicating that cleaved CXCL10 cannot signal through CXCR3. Ultimately, we propose CXCL10 suppression is a convergent mechanism of immune evasion, as Salmonella enterica and Chlamydia trachomatis also suppress CXCL10. This commonality suggests that counteracting CXCL10 suppression may provide a generalizable therapeutic strategy against intracellular pathogens.ImportanceLeishmaniasis, an infectious disease that annually affects over one million people, is caused by intracellular parasites that have evolved to evade the host's attempts to eliminate the parasite. Cutaneous leishmaniasis results in disfiguring skin lesions if the host immune system does not appropriately respond to infection. A family of molecules called chemokines coordinate recruitment of the immune cells required to eliminate infection. Here, we demonstrate a novel mechanism that Leishmania (L.) spp. employ to suppress host chemokines: a Leishmania-encoded protease cleaves chemokines known to recruit T cells that fight off infection. We observe that other common human intracellular pathogens, including Chlamydia trachomatis and Salmonella enterica, reduce levels of the same chemokines, suggesting a strong selective pressure to avoid this component of the immune response. Our study provides new insights into how intracellular pathogens interact with the host immune response to enhance pathogen survival.
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- 2019
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12. Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics
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Kelsey H. Fisher-Wellman, James A. Draper, Michael T. Davidson, Ashley S. Williams, Tara M. Narowski, Dorothy H. Slentz, Olga R. Ilkayeva, Robert D. Stevens, Gregory R. Wagner, Rami Najjar, Mathew D. Hirschey, J. Will Thompson, David P. Olson, Daniel P. Kelly, Timothy R. Koves, Paul A. Grimsrud, and Deborah M. Muoio
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Biology (General) ,QH301-705.5 - Abstract
Summary: Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ∼15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics. : Fisher-Wellman et al. use a recently developed mitochondrial diagnostics platform for deep phenotyping of heart mitochondria derived from three disparate genetic models of protein hyperacylation. Their findings oppose the notion that hyperacylation of the mitochondrial proteome leads to broad-ranging vulnerabilities in respiratory function and bioenergetics. Keywords: mitochondrial diagnostics, lysine acylation, malonylation, ATP synthase
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- 2019
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13. The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins
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Michael N. Davies, Lilja Kjalarsdottir, J. Will Thompson, Laura G. Dubois, Robert D. Stevens, Olga R. Ilkayeva, M. Julia Brosnan, Timothy P. Rolph, Paul A. Grimsrud, and Deborah M. Muoio
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Biology (General) ,QH301-705.5 - Abstract
Lysine acetylation (AcK), a posttranslational modification wherein a two-carbon acetyl group binds covalently to a lysine residue, occurs prominently on mitochondrial proteins and has been linked to metabolic dysfunction. An emergent theory suggests mitochondrial AcK occurs via mass action rather than targeted catalysis. To test this hypothesis, we performed mass spectrometry-based acetylproteomic analyses of quadriceps muscles from mice with skeletal muscle-specific deficiency of carnitine acetyltransferase (CrAT), an enzyme that buffers the mitochondrial acetyl-CoA pool by converting short-chain acyl-CoAs to their membrane permeant acylcarnitine counterparts. CrAT deficiency increased tissue acetyl-CoA levels and susceptibility to diet-induced AcK of broad-ranging mitochondrial proteins, coincident with diminished whole body glucose control. Sub-compartment acetylproteome analyses of muscles from obese mice and humans showed remarkable overrepresentation of mitochondrial matrix proteins. These findings reveal roles for CrAT and L-carnitine in modulating the muscle acetylproteome and provide strong experimental evidence favoring the nonenzymatic carbon pressure model of mitochondrial AcK.
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- 2016
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14. Erratum for Hardison et al., 'Transient Nutrient Deprivation Promotes Macropinocytosis-Dependent Intracellular Bacterial Community Development'
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Rachael L. Hardison, Derek R. Heimlich, Alistair Harrison, Wandy L. Beatty, Sarah Rains, M. Arthur Moseley, J. Will Thompson, Sheryl S. Justice, and Kevin M. Mason
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Microbiology ,QR1-502 - Published
- 2018
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15. Transient Nutrient Deprivation Promotes Macropinocytosis-Dependent Intracellular Bacterial Community Development
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Rachael L. Hardison, Derek R. Heimlich, Alistair Harrison, Wandy L. Beatty, Sarah Rains, M. Arthur Moseley, J. Will Thompson, Sheryl S. Justice, and Kevin M. Mason
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Haemophilus ,NTHI ,endolysosomal pathway ,host cell invasion ,intracellular bacterial community ,macropinocytosis ,Microbiology ,QR1-502 - Abstract
ABSTRACT Nutrient limitation restricts bacterial growth in privileged sites such as the middle ear. Transient heme-iron restriction of nontypeable Haemophilus influenzae (NTHI), the major causative agent of chronic and recurrent otitis media (OM), promotes new and diverse phenotypes that can influence planktonic, biofilm, and intracellular lifestyles of NTHI. However, the bacterial responses to nutrient restriction that impact intracellular fate and survival of NTHI are unknown. In this work, we provide evidence for the role of transient heme-iron restriction in promoting the formation of intracellular bacterial communities (IBCs) of NTHI both in vitro and in vivo in a preclinical model of OM. We show that transient heme-iron restriction of NTHI results in significantly increased invasion and intracellular populations that escape or evade the endolysosomal pathway for increased intracellular survival. In contrast, NTHI continuously exposed to heme-iron traffics through the endolysosomal pathway for degradation. The use of pharmacological inhibitors revealed that prior heme-iron status does not appear to influence NTHI internalization through endocytic pathways. However, inhibition of macropinocytosis altered the intracellular fate of transiently restricted NTHI for degradation in the endolysosomal pathway. Furthermore, prevention of macropinocytosis significantly reduced the number of IBCs in cultured middle ear epithelial cells, providing evidence for the feasibility of this approach to reduce OM persistence. These results reveal that microenvironmental cues can influence the intracellular fate of NTHI, leading to new mechanisms for survival during disease progression. IMPORTANCE Otitis media is the most common bacterial infection in childhood. Current therapies are limited in the prevention of chronic or recurrent otitis media which leads to increased antibiotic exposure and represents a significant socioeconomic burden. In this study, we delineate the effect of nutritional limitation on the intracellular trafficking pathways used by nontypeable Haemophilus influenzae (NTHI). Moreover, transient limitation of heme-iron led to the development of intracellular bacterial communities that are known to contribute to persistence and recurrence in other diseases. New approaches for therapeutic interventions that reduce the production of intracellular bacterial communities and promote trafficking through the endolysosomal pathway were revealed through the use of pharmacological inhibition of macropinocytosis. This work demonstrates the importance of an intracellular niche for NTHI and provides new approaches for intervention for acute, chronic, and recurring episodes of otitis media.
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- 2018
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16. Site-specific analysis of protein S-acylation by resin-assisted capture[S]
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Michael T. Forrester, Douglas T. Hess, J. Will Thompson, Rainbo Hultman, M. Arthur Moseley, Jonathan S. Stamler, and Patrick J. Casey
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acylation ,H-Ras ,lipid ,palmitoylation ,proteomics ,Biochemistry ,QD415-436 - Abstract
Protein S-acylation is a major posttranslational modification whereby a cysteine thiol is converted to a thioester. A prototype is S-palmitoylation (fatty acylation), in which a protein undergoes acylation with a hydrophobic 16 carbon lipid chain. Although this modification is a well-recognized determinant of protein function and localization, current techniques to study cellular S-acylation are cumbersome and/or technically demanding. We recently described a simple and robust methodology to rapidly identify S-nitrosylation sites in proteins via resin-assisted capture (RAC) and provided an initial description of the applicability of the technique to S-acylated proteins (acyl-RAC). Here we expand on the acyl-RAC assay, coupled with mass spectrometry-based proteomics, to characterize both previously reported and novel sites of endogenous S-acylation. Acyl-RAC should therefore find general applicability in studies of both global and individual protein S-acylation in mammalian cells.
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- 2011
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17. Proceedings of the 13th International Newborn Brain Conference: Fetal and/or neonatal brain development, both normal and abnormal
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Khadar Abdi, Ramy Abramsky, Nickie Andescavage, Jephté Bambi, Sudeepta Basu, Cynthia Bearer, Eric J. Benner, Thérèse Biselele, Nikolay Bliznyuk, Jeroen Breckpot, Galen Carey, Agnes Chao, Line Iadsatian Christiansen, Silvia Comani, Pierpaolo Croce, Maarten De Vos, Anneleen Dereymaeker, Laura Dubois, Amelia J. Eisch, Adrian Epstein, Neta Geva, Yael Geva, Marc Gewillig, Sheyenne Gillis, Ronald N. Goldberg, Magnus Gram, Simon Gregory, Danielle Guez-Barber, Masahiro Hayakawa, Nicole Lind Henriksen, Tim Hermans, Reli Hershkovitz, Kristine Holgersen, Bo Holmqvist, Vaibhav Jain, Katrien Jansen, Vinay Kandula, Kushal Kapse, Masahiro Kawaguchi, Abdulhafeez Khair, Mohammad Khazaei, Hiroyuki Kidokoro, Frederico C. Kiffer, Katherine Kisilewicz, Sumire Kumai, Helene Lacaille, David Ley, Catherine Limperopoulos, Sandy Ebba Hallengreen Lindholm, Prosper Lukusa, Rebecca Lundberg, Peter MacFarlane, Pavle Matak, Laetitia Mavinga, Catherine Mayer, Gloire Mbayabo, Takamasa Mitsumatsu, Gerrye Mubungu, Jonathan Murnick, Tomohiko Nakata, Hajime Narita, Parvathi Nataraj, Jun Natsume, Gunnar Naulaers, Rahul Nikam, Niklas Ortenlöf, Katherine Ottolini, Xiaoyu Pan, Stanislava Pankratova, Kelly Pegram, Anna A. Penn, Subechhya Pradhan, Khadijeh Raeisi, Nicholas Rickman, Blaire Rikard, Reut Rotem, Per Torp Sangild, Yoshiaki Sato, Fumi Sawamura, Eilon Shany, Ilan Shelef, Anna Shiraki, Laura Smets, Livia Sura, Ryosuke Suzui, Takeshi Suzuki, Bruno-Paul Tady, Gentaro Taga, Gabriella Tamburro, Liesbeth Thewissen, J. Will Thompson, Thomas Thymann, Cansu Tokat, Claire-Marie Vacher, Cyndi Valdes, Suvi Vallius, Sergei Vatolin, Hama Watanabe, Adi Yehuda Weintraub, Michael Weiss, Hiroyuki Yamamoto, Salem Shimrit Yaniv, Noelle Younge, Sanghee Yun, and Filippo Zappasodi
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Pediatrics, Perinatology and Child Health - Published
- 2022
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18. Supplementary Materials and Methods from CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer
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Stephen J. Freedland, Donald P. McDonnell, Jen-Tsan Chi, Ching-yi Chang, Michael R. Freeman, Laura G. Dubois, J. Will Thompson, Joseph Geradts, Everardo Macias, Jeffery S. Jasper, Rachid Safi, Wen Liu, Erik R. Nelson, and Mahmoud A. Alfaqih
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Reagents and cell culture conditions. Methods for bioinformatics analysis, CYP27A1 IHC, caspase assays and 27HC measurements.
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- 2023
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19. Supplementary Figure S2 from CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer
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Stephen J. Freedland, Donald P. McDonnell, Jen-Tsan Chi, Ching-yi Chang, Michael R. Freeman, Laura G. Dubois, J. Will Thompson, Joseph Geradts, Everardo Macias, Jeffery S. Jasper, Rachid Safi, Wen Liu, Erik R. Nelson, and Mahmoud A. Alfaqih
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Evaluation of CYP27A1 expression in PC cells
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- 2023
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20. Supplementary Table S1-S3 from CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer
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Stephen J. Freedland, Donald P. McDonnell, Jen-Tsan Chi, Ching-yi Chang, Michael R. Freeman, Laura G. Dubois, J. Will Thompson, Joseph Geradts, Everardo Macias, Jeffery S. Jasper, Rachid Safi, Wen Liu, Erik R. Nelson, and Mahmoud A. Alfaqih
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Table S1. CYP27A1 transcript is down-regulated in primary prostate tumors. Table S2. CYP27A1 transcript is down-regulated in metastatic PC relative to primary tumors. Table S3. CYP27A1 transcript levels in hormone sensitive PC relative to hormone resistant PC
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- 2023
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21. Data from CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer
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Stephen J. Freedland, Donald P. McDonnell, Jen-Tsan Chi, Ching-yi Chang, Michael R. Freeman, Laura G. Dubois, J. Will Thompson, Joseph Geradts, Everardo Macias, Jeffery S. Jasper, Rachid Safi, Wen Liu, Erik R. Nelson, and Mahmoud A. Alfaqih
- Abstract
In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662–73. ©2017 AACR.
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- 2023
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22. A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure
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Elizabeth A. Kean, Patrick Luckett, Lori Flores, D. Clark Files, Peter E. Morris, Marie E. Migaud, J. Will Thompson, Raymond J. Langley, Mark N. Gillespie, Matthew Mowry, Lina Purcell, Murphy M. Mostellar, Kevin S. Harrod, James Lovato, Ryan Benton, and Sheetal Gandotra
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Adult ,Male ,Endotype ,Critical Illness ,Science ,Bioinformatics ,Biochemistry ,Article ,Mass Spectrometry ,Sepsis ,Medical research ,medicine ,Metabolome ,Humans ,Metabolomics ,Chromatography, High Pressure Liquid ,Retrospective Studies ,Multidisciplinary ,business.industry ,Middle Aged ,NAD ,medicine.disease ,Pyridoxine ,Acetaminophen ,Acute Disease ,Medicine ,Female ,Thiamine ,NAD+ kinase ,Systems biology ,Energy Metabolism ,Respiratory Insufficiency ,business ,Biomarkers ,NADP ,Drug metabolism ,medicine.drug - Abstract
Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.
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- 2021
23. APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid1
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John Park, and Alzheimer’s Disease Neuroimaging Initiative, Jennifer L. Modliszewski, Arthur Moseley, Michael W. Lutz, Ashley Hall, Stacey Chung, Jeffrey N. Browndyke, Alexander S. Roesler, Victor Cai, Miles Berger, Keith W. VanDusen, Michael J. Devinney, J. Will Thompson, Mary Cooter, Shayan Smani, and David L. Corcoran
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0301 basic medicine ,False discovery rate ,biology ,General Neuroscience ,Neurodegeneration ,C-reactive protein ,General Medicine ,medicine.disease ,Complement system ,03 medical and health sciences ,Psychiatry and Mental health ,Clinical Psychology ,030104 developmental biology ,0302 clinical medicine ,Cerebrospinal fluid ,mental disorders ,Immunology ,medicine ,biology.protein ,Biomarker (medicine) ,Geriatrics and Gerontology ,Alzheimer's disease ,030217 neurology & neurosurgery ,Neuroinflammation - Abstract
Background: APOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. Objective: Characterize cerebrospinal fluid (CSF) proteomic changes related to APOE4 copy number. Methods: We analyzed targeted proteomic data from ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and additional linear models also adjusting for AD clinical status or for CSF Aβ, tau, or p-tau levels. False discovery rate was used to correct for multiple comparisons correction. Results: Increasing APOE4 copy number was associated with a significant decrease in a CRP peptide level across all five models (q
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- 2021
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24. Quantitative Proteomics Links the LRRC59 Interactome to mRNA Translation on the ER Membrane
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Molly M. Hannigan, J. Will Thompson, Christopher V. Nicchitta, Tianli Zheng, and Alyson M. Hoffman
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Proteomics ,Proteasome Endopeptidase Complex ,Proteome ,Endoplasmic Reticulum ,Biochemistry ,Interactome ,Mass Spectrometry ,Analytical Chemistry ,03 medical and health sciences ,Cytosol ,SEC62 ,Cell Line, Tumor ,Protein biosynthesis ,Humans ,Gene Silencing ,Protein Interaction Maps ,RNA, Small Interfering ,Molecular Biology ,Integral membrane protein ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Research ,Endoplasmic reticulum ,Cytoplasmic translation ,030302 biochemistry & molecular biology ,Oligosaccharyltransferase ,Computational Biology ,Membrane Proteins ,Membrane Transport Proteins ,Translation (biology) ,Recombinant Proteins ,Cell biology ,Gene Ontology ,Membrane protein ,Chaperone (protein) ,Protein Biosynthesis ,biology.protein ,Oxidation-Reduction ,Ribosomes ,SEC Translocation Channels - Abstract
Protein synthesis on the endoplasmic reticulum (ER) requires the dynamic coordination of numerous cellular components. Together, resident ER membrane proteins, cytoplasmic translation factors, and both integral membrane and cytosolic RNA-binding proteins operate in concert with membrane-associated ribosomes to facilitate ER-localized translation. Little is known, however, regarding the spatial organization of ER-localized translation. This question is of growing significance as it is now known that ER-bound ribosomes contribute to secretory, integral membrane, and cytosolic protein synthesis alike. To explore this question, we utilized quantitative proximity proteomics to identify neighboring protein networks for the candidate ribosome interactors SEC61β (subunit of the protein translocase), RPN1 (oligosaccharyltransferase subunit), SEC62 (translocation integral membrane protein), and LRRC59 (ribosome binding integral membrane protein). Biotin labeling time course studies of the four BioID reporters revealed distinct labeling patterns that intensified but only modestly diversified as a function of labeling time, suggesting that the ER membrane is organized into discrete protein interaction domains. Whereas SEC61β and RPN1 reporters identified translocon-associated networks, SEC62 and LRRC59 reporters revealed divergent protein interactomes. Notably, the SEC62 interactome is enriched in redox-linked proteins and ER luminal chaperones, with the latter likely representing proximity to an ER luminal chaperone reflux pathway. In contrast, the LRRC59 interactome is highly enriched in SRP pathway components, translation factors, and ER-localized RNA-binding proteins, uncovering a functional link between LRRC59 and mRNA translation regulation. Importantly, analysis of the LRRC59 interactome by native immunoprecipitation identified similar protein and functional enrichments. Moreover, [(35)S]-methionine incorporation assays revealed that siRNA silencing of LRRC59 expression reduced steady state translation levels on the ER by ca. 50%, and also impacted steady state translation levels in the cytosol compartment. Collectively, these data reveal a functional domain organization for the ER and identify a key role for LRRC59 in the organization and regulation of local translation.
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- 2020
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25. Metabolomic Signature as a Predictor of Liver Disease Events in Patients With HIV/HCV Coinfection
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Susanna Naggie, Sam Lusk, Cynthia A. Moylan, Joseph E. Lucas, Laura G. Dubois, J. Will Thompson, M. Arthur Moseley, Meredith Mock, Keyur Patel, and Lisa St. John-Williams
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Male ,0301 basic medicine ,medicine.medical_specialty ,Hepatitis C virus ,HIV Infections ,medicine.disease_cause ,Models, Biological ,Likelihood ratios in diagnostic testing ,Gastroenterology ,Bile Acids and Salts ,End Stage Liver Disease ,Major Articles and Brief Reports ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Spontaneous bacterial peritonitis ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Amino Acids ,Hepatic encephalopathy ,Coinfection ,business.industry ,Fatty Acids ,Middle Aged ,Prognosis ,medicine.disease ,Hepatitis C ,030104 developmental biology ,Infectious Diseases ,Case-Control Studies ,Hepatocellular carcinoma ,Metabolome ,Biomarker (medicine) ,Female ,business ,Biomarkers - Abstract
Background Advanced liver disease due to hepatitis C virus (HCV) is a leading cause of human immunodeficiency virus (HIV)-related morbidity and mortality. There remains a need to develop noninvasive predictors of clinical outcomes in persons with HIV/HCV coinfection. Methods We conducted a nested case-control study in 126 patients with HIV/HCV and utilized multiple quantitative metabolomic assays to identify a prognostic profile that predicts end-stage liver disease (ESLD) events including ascites, hepatic encephalopathy, hepatocellular carcinoma, esophageal variceal bleed, and spontaneous bacterial peritonitis. Each analyte class was included in predictive modeling, and area under the receiver operator characteristic curves (AUC) and accuracy were determined. Results The baseline model including demographic and clinical data had an AUC of 0.79. Three models (baseline plus amino acids, lipid metabolites, or all combined metabolites) had very good accuracy (AUC, 0.84–0.89) in differentiating patients at risk of developing an ESLD complication up to 2 years in advance. The all combined metabolites model had sensitivity 0.70, specificity 0.85, positive likelihood ratio 4.78, and negative likelihood ratio 0.35. Conclusions We report that quantification of a novel set of metabolites may allow earlier identification of patients with HIV/HCV who have the greatest risk of developing ESLD clinical events.
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- 2020
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26. Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome
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Rima Kaddurah-Daouk, Kevin Huynh, Matthias Arnold, David A. Bennett, Siamak MahmoudianDehkordi, Lisa St John Williams, J. Will Thompson, Jon B. Toledo, Colette Blach, Jessica D. Tenenbaum, Rebecca Baillie, Barbara Brauner, Roberta Diaz Brinton, Andrew J. Saykin, Jan Krumsiek, Kwangsik Nho, Alexandra Kueider-Paisley, Leslie M. Shaw, Michael W. Weiner, Gabi Kastenmüller, Ralph N. Martins, P. Murali Doraiswamy, M. Arthur Moseley, Tyler Massaro, Peter J. Meikle, Eugenia Trushina, Xianlin Han, Rui Chang, Gregory Louie, and John Q. Trojanowski
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0301 basic medicine ,Apolipoprotein E ,Male ,Aging ,General Physics and Astronomy ,Physiology ,Disease ,Neurodegenerative ,Alzheimer's Disease ,Cohort Studies ,0302 clinical medicine ,Genotype ,lcsh:Science ,Multidisciplinary ,Alzheimer's disease ,3. Good health ,Mitochondria ,Blood ,Neurological ,Metabolome ,Female ,lipids (amino acids, peptides, and proteins) ,Science ,Predictive markers ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Metabolomics ,Insulin resistance ,Apolipoproteins E ,Sex Factors ,Alzheimer Disease ,medicine ,Acquired Cognitive Impairment ,Genetics ,Dementia ,Humans ,Aged ,business.industry ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,General Chemistry ,medicine.disease ,Brain Disorders ,030104 developmental biology ,Good Health and Well Being ,Positron-Emission Tomography ,lcsh:Q ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine., Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.
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- 2020
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27. Skyline for Small Molecules: A Unifying Software Package for Quantitative Metabolomics
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Pankaj Kapahi, Karina Ky, M. Arthur Moseley, Lisa St. John-Williams, Vagisha Sharma, Laura G. Dubois, Kevin M. Perrott, Carol A. Colton, Brendan MacLean, J. Will Thompson, Kendra J. Adams, Neelanjan Bose, Brian S. Pratt, Michael J. MacCoss, and Birgit Schilling
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Proteomics ,0301 basic medicine ,Computer science ,computer.software_genre ,Biochemistry ,Mass Spectrometry ,Article ,03 medical and health sciences ,Data visualization ,Software ,Metabolomics ,Amino Acid Sequence ,Skyline ,Data processing ,030102 biochemistry & molecular biology ,business.industry ,InformationSystems_DATABASEMANAGEMENT ,General Chemistry ,Software package ,Small molecule ,030104 developmental biology ,Workflow ,Data mining ,business ,computer - Abstract
Vendor-independent software tools for quantification of small molecules and metabolites are lacking, especially for targeted analysis workflows. Skyline is a freely available, open-source software tool for targeted quantitative mass spectrometry method development and data processing with a ten-year history supporting 6 major instrument vendors. Designed initially for proteomic analysis, we describe the expansion of Skyline to data for small molecule analysis, including selected reaction monitoring (SRM), high-resolution mass spectrometry (HRMS), and calibrated quantification. This fundamental expansion of Skyline from a peptide-sequence centric tool to a molecule-centric tool makes it agnostic to the source of the molecule while retaining Skyline features critical for workflows in both peptide and more general biomolecular research. The data visualization and interrogation features already available in Skyline - such as peak picking, chromatographic alignment, and transition selection - have been adapted to support small molecule data, including metabolomics. Herein, we explain the conceptual workflow for small molecule analysis using Skyline, demonstrate Skyline performance benchmarked against a comparable instrument vendor software tool, and present additional real-world applications. Further, we include step-by-step instructions on using Skyline for small molecule quantitative method development and data analysis on data acquired with a variety of mass spectrometers from multiple instrument vendors.
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- 2020
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28. Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh Syndrome
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Alessandro Bitto, Anthony S. Grillo, Ian B. Stanaway, Bao M. G. Nguyen, Kejun Ying, Herman Tung, Kaleb Smith, Ngoc Tran, Gunnar Velikanje, Silvan R. Urfer, Jessica M. Snyder, Ernst-Bernhard Kayser, Lu Wang, Daniel L. Smith, J. Will Thompson, Laura DuBois, William DePaolo, and Matt Kaeberlein
- Abstract
SummaryMitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological aging process. Rapamycin, a drug that increases lifespan and health during normative aging also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh Syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh Syndrome. Here we show that another drug that extends lifespan and delays normative aging in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression. This study provides the first evidence that alteration of the gut microbiome may impact severe mitochondrial disease and provides further support for the model that biological aging and severe mitochondrial disorders share underlying common mechanisms.
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- 2022
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29. Cancer Cell-Derived GABA Promotes β-Catenin-Mediated Tumor Growth and Immunosuppression
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De Huang, Yan Wang, J. Will Thompson, Tao Yin, Peter B. Alexander, Diyuan Qin, Poorva Mudgal, Haiyang Wu, Yaosi Liang, Lianmei Tan, Christopher Pan, Lifeng Yuan, Ying Wan, Qi-Jing Li, and Xiao-Fan Wang
- Subjects
Programmed Cell Death 1 Receptor ,Mice, Nude ,Cell Communication ,CD8-Positive T-Lymphocytes ,Article ,Lymphocytes, Tumor-Infiltrating ,Neoplasms ,Tumor Microenvironment ,Animals ,Humans ,Immune Checkpoint Inhibitors ,Wnt Signaling Pathway ,beta Catenin ,gamma-Aminobutyric Acid ,Cell Proliferation ,Glycogen Synthase Kinase 3 beta ,Glutamate Decarboxylase ,Cell Biology ,HCT116 Cells ,Xenograft Model Antitumor Assays ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,HEK293 Cells ,Receptors, GABA-B ,A549 Cells ,Drug Resistance, Neoplasm ,Female ,Tumor Escape ,HT29 Cells ,Signal Transduction - Abstract
Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for synthesis of γ-aminobutyric acid (GABA), a prominent neurotransmitter, in non-nervous tissues. Clinical sample analysis reveals increased GABA levels predicting poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway by which GABA activates the GABA(B) receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signaling. This GABA-mediated β-catenin activation both stimulates tumor cell proliferation and suppresses CD8(+) T cell intratumoral infiltration, such that targeting GAD1 or GABA(B)R in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover an unexpected signaling role for tumor-derived GABA beyond its classic function as a neurotransmitter that can be exploited pharmacologically to reverse immunosuppression.
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- 2022
30. Proceedings of the 13th International Newborn Brain Conference: Fetal and/or neonatal brain development, both normal and abnormal
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Khadar, Abdi, Ramy, Abramsky, Nickie, Andescavage, Jephté, Bambi, Sudeepta, Basu, Cynthia, Bearer, Eric J, Benner, Thérèse, Biselele, Nikolay, Bliznyuk, Jeroen, Breckpot, Galen, Carey, Agnes, Chao, Line Iadsatian, Christiansen, Silvia, Comani, Pierpaolo, Croce, Maarten, De Vos, Anneleen, Dereymaeker, Laura, Dubois, Amelia J, Eisch, Adrian, Epstein, Neta, Geva, Yael, Geva, Marc, Gewillig, Sheyenne, Gillis, Ronald N, Goldberg, Magnus, Gram, Simon, Gregory, Danielle, Guez-Barber, Masahiro, Hayakawa, Nicole Lind, Henriksen, Tim, Hermans, Reli, Hershkovitz, Kristine, Holgersen, Bo, Holmqvist, Vaibhav, Jain, Katrien, Jansen, Vinay, Kandula, Kushal, Kapse, Masahiro, Kawaguchi, Abdulhafeez, Khair, Mohammad, Khazaei, Hiroyuki, Kidokoro, Frederico C, Kiffer, Katherine, Kisilewicz, Sumire, Kumai, Helene, Lacaille, David, Ley, Catherine, Limperopoulos, Sandy Ebba Hallengreen, Lindholm, Prosper, Lukusa, Rebecca, Lundberg, Peter, MacFarlane, Pavle, Matak, Laetitia, Mavinga, Catherine, Mayer, Gloire, Mbayabo, Takamasa, Mitsumatsu, Gerrye, Mubungu, Jonathan, Murnick, Tomohiko, Nakata, Hajime, Narita, Parvathi, Nataraj, Jun, Natsume, Gunnar, Naulaers, Rahul, Nikam, Niklas, Ortenlöf, Katherine, Ottolini, Xiaoyu, Pan, Stanislava, Pankratova, Kelly, Pegram, Anna A, Penn, Subechhya, Pradhan, Khadijeh, Raeisi, Nicholas, Rickman, Blaire, Rikard, Reut, Rotem, Per Torp, Sangild, Yoshiaki, Sato, Fumi, Sawamura, Eilon, Shany, Ilan, Shelef, Anna, Shiraki, Laura, Smets, Livia, Sura, Ryosuke, Suzui, Takeshi, Suzuki, Bruno-Paul, Tady, Gentaro, Taga, Gabriella, Tamburro, Liesbeth, Thewissen, J Will, Thompson, Thomas, Thymann, Cansu, Tokat, Claire-Marie, Vacher, Cyndi, Valdes, Suvi, Vallius, Sergei, Vatolin, Hama, Watanabe, Adi Yehuda, Weintraub, Michael, Weiss, Hiroyuki, Yamamoto, Salem Shimrit, Yaniv, Noelle, Younge, Sanghee, Yun, and Filippo, Zappasodi
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Fetus ,Pregnancy ,Infant, Newborn ,Brain ,Humans ,Female ,Prenatal Care ,Head - Abstract
ispartof: J Neonatal Perinatal Med vol:15 issue:2 pages:411-426 ispartof: location:Netherlands status: published
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- 2022
31. A comparative analysis of egg provisioning using mass spectrometry during rapid life history evolution in sea urchins
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Phillip L Davidson, J. Will Thompson, Maria Byrne, Matthew W. Foster, M. Arthur Moseley, and Gregory A. Wray
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0106 biological sciences ,0301 basic medicine ,Zoology ,010603 evolutionary biology ,01 natural sciences ,Article ,Life history theory ,03 medical and health sciences ,Tandem Mass Spectrometry ,biology.animal ,Animals ,Life history ,Sea urchin ,Ecology, Evolution, Behavior and Systematics ,Ovum ,Diacylglycerol kinase ,Lytechinus variegatus ,Larva ,biology ,Marine larval ecology ,Marine invertebrates ,biology.organism_classification ,Adaptation, Physiological ,Biological Evolution ,030104 developmental biology ,Sea Urchins ,Lipidomics ,Chromatography, Liquid ,Developmental Biology - Abstract
A dramatic life history switch that has evolved numerous times in marine invertebrates is the transition from planktotrophic (feeding) to lecithotrophic (nonfeeding) larval development—an evolutionary tradeoff with many important developmental and ecological consequences. To attain a more comprehensive understanding of the molecular basis for this switch, we performed untargeted lipidomic and proteomic liquid chromatography-tandem mass spectrometry on eggs and larvae from three sea urchin species: the lecithotroph Heliocidaris erythrogramma, the closely related planktotroph Heliocidaris tuberculata, and the distantly related planktotroph Lytechinus variegatus. We identify numerous molecular-level changes possibly associated with the evolution of lecithotrophy in H. erythrogramma. We find the massive lipid stores of H. erythrogramma eggs are largely composed of low-density, diacylglycerol ether lipids that, contrary to expectations, appear to support postmetamorphic development and survivorship. Rapid premetamorphic development in this species may instead be powered by upregulated carbohydrate metabolism or triacylglycerol metabolism. We also find proteins involved in oxidative stress regulation are upregulated in H. erythrogramma eggs, and apoB-like lipid transfer proteins may be important for echinoid oogenic nutrient provisioning. These results demonstrate how mass spectrometry can enrich our understanding of life history evolution and organismal diversity by identifying specific molecules associated with distinct life history strategies and prompt new hypotheses about how and why these adaptations evolve.
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- 2019
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32. Metabolomic Patterns in Adolescents With Mild to Moderate CKD
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Shannon Haymond, Craig B. Langman, David C. Lin, Bradley A. Warady, Susan L. Furth, Ellen R. Brooks, Lisa St. John-Williams, and J. Will Thompson
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03 medical and health sciences ,0302 clinical medicine ,Text mining ,Metabolomics ,Nephrology ,business.industry ,030232 urology & nephrology ,MEDLINE ,Research Letter ,Medicine ,030204 cardiovascular system & hematology ,business ,Bioinformatics - Published
- 2019
33. Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction
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Jeffrey N. Browndyke, Leah Acker, Madco-Pc Investigators, J. Will Thompson, Yi-Ju Li, Niccolò Terrando, Eugene W. Moretti, Joseph P. Mathew, Keith W. VanDusen, Michael J. Devinney, Quintin J Quinones, Ashley Hall, Jerrold H. Levy, Sarah Hiles, M. Arthur Moseley, Kamrouz Ghadimi, Mary Cooter, Stacey Chung, Victor Cai, and Miles Berger
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0301 basic medicine ,Male ,Proteome ,Disease ,Proteomics ,Bioinformatics ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Postoperative Cognitive Complications ,Tandem Mass Spectrometry ,Medicine ,Humans ,Neuroinflammation ,Aged ,business.industry ,General Neuroscience ,General Medicine ,Perioperative ,medicine.disease ,Pathophysiology ,Psychiatry and Mental health ,Clinical Psychology ,030104 developmental biology ,Case-Control Studies ,Female ,Geriatrics and Gerontology ,business ,Postoperative cognitive dysfunction ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Background: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1–12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD. Objective: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD. Methods: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis. Results: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus without POCD (q
- Published
- 2021
34. Alterations in acylcarnitines, amines, and lipids inform about the mechanism of action of citalopram/escitalopram in major depression
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Boadie W. Dunlop, Lisa St. John-Williams, Michelle K. Skime, Gregory Louie, W. Edward Craighead, J. Will Thompson, Rima Kaddurah-Daouk, Mark A. Frye, Xianlin Han, Rebecca Baillie, Sudeepa Bhattacharyya, Siamak MahmoudianDehkordi, Richard M. Weinshilboum, A. John Rush, Matthias Arnold, Patricio Riva-Posse, Ahmed T. Ahmed, M. Arthur Moseley, William M. McDonald, Ranga R. Krishnan, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, Amsterdam Neuroscience - Complex Trait Genetics, Psychiatry, and APH - Digital Health
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medicine.medical_specialty ,Sarcosine ,Serotonin uptake ,Scientific community ,Clinical Sciences ,Citalopram ,Article ,lcsh:RC321-571 ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Internal medicine ,Carnitine ,medicine ,Escitalopram ,Humans ,Psychology ,Amines ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,Depressive Disorder, Major ,Mood Disorders Precision Medicine Consortium ,Depressive Disorder ,business.industry ,Depression ,Hamilton Rating Scale for Depression ,Major ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Lipids ,Antidepressive Agents ,Brain Disorders ,Psychiatry and Mental health ,Endocrinology ,Mental Health ,chemistry ,Mechanism of action ,6.1 Pharmaceuticals ,Public Health and Health Services ,Major depressive disorder ,Serotonin ,medicine.symptom ,business ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium-chain and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines—including arginine, proline, and methionine sulfoxide—were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism, and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17 ≤ 7) and those who gained no meaningful benefits (17). Remitters exhibited (a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine, and serotonin; and (b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2, and PC aa C36:4. These findings suggest that mitochondrial energetics—including acylcarnitine metabolism, transport, and its link to β-oxidation—and lipid membrane remodeling may play roles in SSRI treatment response.
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- 2021
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35. KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPβ Signaling Pathway
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Kaitlyn Thatcher, J. Will Thompson, Punashi Dutta, Karthik M. Kodigepalli, Joy Lincoln, Sarah Rains, Robert B. Hinton, Stephanie LaHaye, and Casey Nagel
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0301 basic medicine ,Physiology ,Receptors, Cytoplasmic and Nuclear ,030204 cardiovascular system & hematology ,Karyopherins ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Axin Protein ,AXIN1 ,Medicine ,Animals ,Viability assay ,Heart valve ,Nuclear export signal ,Transcription factor ,Klotho Proteins ,Wnt Signaling Pathway ,business.industry ,Wnt signaling pathway ,Drug Repositioning ,Calcinosis ,Aortic Valve Stenosis ,Triazoles ,030104 developmental biology ,medicine.anatomical_structure ,Hydrazines ,CCAAT-Binding Factor ,Aortic Valve ,Cancer research ,Aortic valve calcification ,Signal transduction ,Cardiology and Cardiovascular Medicine ,business - Abstract
Rationale: Calcific aortic valve disease (CAVD) affects >5.2 million people in the United States. The only effective treatment is surgery, and this comes with complications and no guarantee of long-term success. Objective: Outcomes from pharmacological initiatives remain unsubstantiated and, therefore, the aim of this study is to determine if repurposing a selective XPO1 (exportin-1) inhibitor drug (KPT-330) is beneficial in the treatment of CAVD. Methods and Results: We show that KPT-330 prevents, attenuates, and mitigates calcific nodule formation in heart valve interstitial cells in vitro and prevents CAVD in Klotho −/− mice. Using RNA-sequencing and mass spectrometry, we show that KPT-330’s beneficial effect is mediated by inhibiting nuclear export of the C/EBPβ (transcription factor CCAAT/enhancing-binding protein) in valve interstitial cells, leading to repression of canonical Wnt signaling, in part, through activation of the Wnt antagonist Axin1 , and a subsequent decrease in proosteogenic markers and cell viability. Conclusions: Our findings have met a critical need to discover alternative, pharmacological-based therapies in the treatment of CAVD.
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- 2021
36. Likelihood ratio statistics for gene set enrichment in Alzheimer's disease pathways
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Michael W. Lutz, Kendra J. Adams, Gauri Kamat, Sayan Mukherjee, Jordan Bryan, Carol A. Colton, Alzheimer’s Disease Neuroimaging Initiative, W. Kirby Gottschalk, Alexandra Badea, Arpita Mandan, and J. Will Thompson
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0301 basic medicine ,Epidemiology ,Context (language use) ,Disease ,Biology ,Logistic regression ,Article ,Biological pathway ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,0302 clinical medicine ,Sex Factors ,Developmental Neuroscience ,Alzheimer Disease ,Covariate ,Statistics ,Animals ,Humans ,Set (psychology) ,Statistical hypothesis testing ,Models, Statistical ,Health Policy ,Linear model ,Age Factors ,Psychiatry and Mental health ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Neurology (clinical) ,Geriatrics and Gerontology ,030217 neurology & neurosurgery - Abstract
Introduction The study of Alzheimer's disease (AD) has revealed biological pathways with implications for disease neuropathology and pathophysiology. These pathway-level effects may also be mediated by individual characteristics or covariates such as age or sex. Evaluation of AD biological pathways in the context of interactions with these covariates is critical to the understanding of AD as well as the development of model systems used to study the disease. Methods Gene set enrichment methods are powerful tools used to interpret gene-level statistics at the level of biological pathways. We introduce a method for quantifying gene set enrichment using likelihood ratio-derived test statistics (gsLRT), which accounts for sample covariates like age and sex. We then use our method to test for age and sex interactions with protein expression levels in AD and to compare the pathway results between human and mouse species. Results Our method, based on nested logistic regressions is competitive with the existing standard for gene set testing in the context of linear models and complex experimental design. The gene sets we identify as having a significant association with AD-both with and without additional covariate interactions-are validated by previous studies. Differences between gsLRT results on mouse and human datasets are observed. Discussion Characterizing biological pathways involved in AD builds on the important work involving single gene drivers. Our gene set enrichment method finds pathways that are significantly related to AD while accounting for covariates that may be relevant to disease development. The method highlights commonalities and differences between human AD and mouse models, which may inform the development of higher fidelity models for the study of AD.
- Published
- 2021
37. APOE4 Copy Number-Dependent Proteomic changes in the Cerebrospinal Fluid
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Mary Cooter, Victor Cai, Alzheimer’s Disease Neuroimaging Initiative, Arthur Moseley, Michael J. Devinney, Alexander S. Roesler, Jennifer L. Modliszeski, Stacey Chung, John Park, J. Will Thompson, Keith W. VanDusen, Shayan Smani, David L. Corcoran, Jeffrey N. Browndyke, Miles Berger, Ashley Hall, and Michael W. Lutz
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False discovery rate ,medicine.medical_specialty ,Endocrinology ,Future studies ,Cerebrospinal fluid ,Internal medicine ,Multiple comparisons problem ,Linear regression ,Disease risk ,medicine ,Biology ,Neuroinflammation ,Complement system - Abstract
BackgroundAPOE4 has been hypothesized to increase Alzheimer’s disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear.ObjectivesTo characterize CSF proteomic changes as a function of APOE4 copy number.MethodsWe analyzed targeted proteomic data obtained on ADNI CSF samples using a linear regression model adjusting for age, sex, and APOE4 copy number, and a second linear model also adjusting for AD clinical status. False Discovery Rate (FDR) was used to correct for multiple comparisons.ResultsIn the first model, increasing APOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.006), and significant expression increases in peptides from ALDOA, CH3L1 (YKL-40), and FABPH (qAPOE4 copy number was associated with significant expression decreases in a CRP peptide (q=0.009). In both models, increased APOE4 copy number was associated with trends towards lower expression of all 24 peptides from all 8 different complement proteins measured here, although none of these differences were statistically significant. The odds of this happening by chance for 24 unrelated peptides would be less than 1 in 16 million.ConclusionsIncreasing APOE4 copy number was associated with decreased CSF CRP levels and increased CSF ALDOA, CH3L1 and FABH levels; the CRP decrease remained significant after controlling for AD clinical status. Increased APOE4 copy number may also be associated with decreased CSF complement pathway protein levels, a hypothesis for investigation in future studies.
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- 2020
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38. The effect of pathogen inactivation on cryoprecipitate: a functional and quantitative evaluation
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Reed W, Kamyszek, Matthew W, Foster, Brooke A, Evans, Keaton, Stoner, Jessica, Poisson, Amudan J, Srinivasan, J Will, Thompson, M Arthur, Moseley, Micah J, Mooberry, and Ian J, Welsby
- Subjects
Blood Platelets ,Cryopreservation ,Blood-Borne Infections ,Microbial Viability ,Photosensitizing Agents ,Photochemistry ,Ultraviolet Rays ,Blood Safety ,Thrombin ,Blood Proteins ,Thrombelastography ,Thromboplastin ,Plasma ,Blood Preservation ,Cell-Derived Microparticles ,Furocoumarins ,Blood Component Removal ,Blood-Borne Pathogens ,Humans ,Virus Inactivation ,Blood Components and Regenerative Medicine - Abstract
As a pooled donor blood product, cryoprecipitate (cryo) carries risks of pathogen transmission. Pathogen inactivation (PI) improves the safety of cryoprecipitate, but its effects on haemostatic properties remain unclear. This study investigated protein expression in samples of pathogen inactivated cryoprecipitate (PI-cryo) using non-targeted quantitative proteomics and in vitro haemostatic capacity of PI-cryo.Whole blood (WB)- and apheresis (APH)-derived plasma was subject to PI with INTERCEPTOver 300 proteins were quantified across paired PI-cryo and controls. PI did not alter the expression of coagulation factors, but levels of platelet-derived proteins and platelet-derived MPs were markedly lower in the WB PI-cryo group. Compared to controls, WB (but not APH) cryo samples demonstrated significantly lower MP prothrombinase activity, prolonged clotting time, and lower clot firmness on thromboelastometry after PI. However, PI did not affect overall thrombin generation variables in either group.Data from this study suggest that PI via INTERCEPT
- Published
- 2020
39. Alterations in Acylcarnitines, Amines, and Lipids Inform about Mechanism of Action of Citalopram/Escitalopram in Major Depression
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Siamak MahmoudianDehkordi, Mark A. Frye, A. John Rush, William M. McDonald, Xianlin Han, Gregory Louie, Ahmed T. Ahmed, Rima Kaddurah-Daouk, J. Will Thompson, Richard M. Weinshilboum, M. Arthur Moseley, Boadie W. Dunlop, Lisa St. John-Williams, W. Edward Craighead, Patricio Riva-Posse, Rebecca Baillie, Sudeepa Bhattacharyya, Michelle K. Skime, Matthias Arnold, and Ranga R. Krishnan
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Serotonin uptake ,business.industry ,Hamilton Rating Scale for Depression ,Pharmacology ,Citalopram ,medicine.disease ,Mechanism of action ,Urea cycle ,medicine ,Major depressive disorder ,Escitalopram ,Serotonin ,medicine.symptom ,business ,medicine.drug - Abstract
Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for major depressive disorder (MDD), yet their mechanisms of action are not fully understood and their therapeutic benefit varies among individuals. We used a targeted metabolomics approach utilizing a panel of 180 metabolites to gain insights into mechanisms of action and response to citalopram/escitalopram. Plasma samples from 136 participants with MDD enrolled into the Mayo Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) were profiled at baseline and after 8 weeks of treatment. After treatment, we saw increased levels of short-chain acylcarnitines and decreased levels of medium- and long-chain acylcarnitines, suggesting an SSRI effect on β-oxidation and mitochondrial function. Amines – including arginine, proline, and methionine-sulfoxide – were upregulated while serotonin and sarcosine were downregulated, suggesting an SSRI effect on urea cycle, one-carbon metabolism and serotonin uptake. Eighteen lipids within the phosphatidylcholine (PC aa and ae) classes were upregulated. Changes in several lipid and amine levels correlated with changes in 17-item Hamilton Rating Scale for Depression scores (HRSD17). Differences in metabolic profiles at baseline and post-treatment were noted between participants who remitted (HRSD17≤7) and those who gained no meaningful benefits (17). Remitters exhibited a) higher baseline levels of C3, C5, alpha-aminoadipic acid, sarcosine and serotonin; and b) higher week-8 levels of PC aa C34:1, PC aa C34:2, PC aa C36:2 and PC aa C36:4. These findings suggest that mitochondrial energetics – including acylcarnitine metabolism, transport and its link to β-oxidation – and lipid membrane remodeling may play roles in SSRI treatment response.
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- 2020
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40. Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer
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Stephanie N. Phelps, Amy E. Decker, J. Will Thompson, Nathaniel W. Mabe, Ryan Lupo, Douglas B. Fox, and James V. Alvarez
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0301 basic medicine ,Epithelial-Mesenchymal Transition ,Histone Deacetylase 2 ,Mice, Nude ,Antineoplastic Agents ,Breast Neoplasms ,Histone Deacetylase 1 ,Biology ,Mice ,03 medical and health sciences ,Breast cancer ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Epigenome editing ,Animals ,Humans ,Gene silencing ,Enhancer of Zeste Homolog 2 Protein ,Gene Silencing ,Epigenetics ,Tumor Suppressor Proteins ,Twist-Related Protein 1 ,EZH2 ,Nuclear Proteins ,General Medicine ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Histone ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,Female ,Neoplasm Recurrence, Local ,Apoptosis Regulatory Proteins ,Research Article ,Bivalent chromatin - Abstract
Tumor relapse is the leading cause of death in breast cancer, largely due to the fact that recurrent tumors are frequently resistant to chemotherapy. We previously reported that downregulation of the proapoptotic protein Par-4 promotes tumor recurrence in genetically engineered mouse models of breast cancer recurrence. In the present study, we examined the mechanism and functional significance of Par-4 downregulation in recurrent tumors. We found that epithelial-to-mesenchymal transition (EMT) promotes epigenetic silencing of Par-4 in recurrent tumors. Par-4 silencing proceeded through binding of the EMT transcription factor Twist to the Par-4 promoter, where Twist induced a unique bivalent chromatin domain. This bivalent configuration conferred plasticity at the Par-4 promoter, and Par-4 silencing could be reversed with pharmacologic inhibitors of Ezh2 and HDAC1/2. Using an epigenome editing approach to reexpress Par-4 by specifically reversing the histone modifications found in recurrent tumors, we found that Par-4 reexpression sensitized recurrent tumors to chemotherapy in vitro and in vivo. Upon reexpression, Par-4 bound to the protein phosphatase PP1, caused widespread changes in phosphorylation of cytoskeletal proteins, and cooperated with microtubule-targeting drugs to induce mitotic defects. These results identify Twist-induced epigenetic silencing of Par-4 as a targetable axis that promotes chemoresistance in recurrent breast cancer.
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- 2018
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41. Switching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death
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Linhui Zhai, Lili Qian, Yi Ding, Jing Hu, Lifeng Yuan, Handan Xiang, Juan Liu, Xiaojing Liu, J. Will Thompson, Xiao-Qiong Chen, De Huang, Qing-Peng Kong, Xiao-Fan Wang, Minjia Tan, and Yonghan He
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0301 basic medicine ,Senescence ,Programmed cell death ,HEK 293 cells ,Regulator ,Cell Biology ,Biology ,Cell fate determination ,medicine.disease_cause ,Article ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,medicine ,Signal transduction ,Molecular Biology ,Reprogramming ,Oxidative stress - Abstract
Cellular senescence is a fundamental cell fate playing a significant role throughout the natural aging process. However, the molecular determinants distinguishing senescence from other cell-cycle arrest states such as quiescence and post-mitotic state, and the specified mechanisms underlying cell-fate decisions towards senescence versus cell death in response to cellular stress stimuli remain less understood. Employing multi-omics approaches, we revealed that switching off the specific mitochondrial processing machinery involving the peptidase IMMP2L serves as the foundation of the senescence program, which was also observed during the mammalian aging process. Mechanistically, we demonstrate that IMMP2L processes and thus activates at least two substrates, mitochondrial metabolic enzyme glycerol-3-phosphate dehydrogenase (GPD2) and cell death regulator apoptosis-inducing factor (AIF). For cells destined to senesce, concerted shutdown of the IMMP2L-GPD2 and IMMP2L-AIF signaling axes collaboratively drives the senescent process by reprogramming mitochondria-associated redox status, phospholipid metabolism and signaling network, and simultaneously blocking cell death under oxidative stress conditions.
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- 2018
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42. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells
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Hannah B. McDowell, Suzanne E. Wardell, Ching-Yi Chang, Erik R. Nelson, Donald P. McDonnell, J. Will Thompson, Yen-Rei A. Yu, Ruchita V. Pillai, Michael D. Gunn, Amy E. Baek, Sisi He, Jongsook Kim Kemper, Laura G. Dubois, Patrick Sullivan, and Sanghoon Kwon
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0301 basic medicine ,Myeloid ,Oxysterol ,Science ,General Physics and Astronomy ,Breast Neoplasms ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Cholesterol, Dietary ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Breast cancer ,Cell Line, Tumor ,CYP27A1 ,polycyclic compounds ,medicine ,Animals ,Humans ,Myeloid Cells ,Obesity ,Neoplasm Metastasis ,lcsh:Science ,Multidisciplinary ,Carcinoma ,Cancer ,General Chemistry ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Hydroxycholesterols ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,27-Hydroxycholesterol ,Cancer research ,bacteria ,lcsh:Q ,Female ,lipids (amino acids, peptides, and proteins) - Abstract
Obesity and elevated circulating cholesterol are risk factors for breast cancer recurrence, while the use of statins, cholesterol biosynthesis inhibitors widely used for treating hypercholesterolemia, is associated with improved disease-free survival. Here, we show that cholesterol mediates the metastatic effects of a high-fat diet via its oxysterol metabolite, 27-hydroxycholesterol. Ablation or inhibition of CYP27A1, the enzyme responsible for the rate-limiting step in 27-hydroxycholesterol biosynthesis, significantly reduces metastasis in relevant animal models of cancer. The robust effects of 27-hydroxycholesterol on metastasis requires myeloid immune cell function, and it was found that this oxysterol increases the number of polymorphonuclear-neutrophils and γδ-T cells at distal metastatic sites. The pro-metastatic actions of 27-hydroxycholesterol requires both polymorphonuclear-neutrophils and γδ-T cells, and 27-hydroxycholesterol treatment results in a decreased number of cytotoxic CD8+T lymphocytes. Therefore, through its actions on γδ-T cells and polymorphonuclear-neutrophils, 27-hydroxycholesterol functions as a biochemical mediator of the metastatic effects of hypercholesterolemia., High cholesterol is a risk factor for breast cancer recurrence. Here the authors show that cholesterol promotes breast cancer metastasis via its metabolite 27-hydroxycholesterol (27HC) that acts on immune myeloid cells residing at the distal metastatic sites, thus promoting an immune suppressive environment.
- Published
- 2017
43. CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer
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Jen-Tsan Chi, Mahmoud A. Alfaqih, Jeffery S. Jasper, Rachid Safi, Joseph Geradts, Erik R. Nelson, Stephen J. Freedland, Wen Liu, Everardo Macias, J. Will Thompson, Donald P. McDonnell, Michael R. Freeman, Ching-Yi Chang, and Laura G. Dubois
- Subjects
Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Receptor expression ,Biology ,Gene Expression Regulation, Enzymologic ,Mice ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Cell Line, Tumor ,Internal medicine ,CYP27A1 ,medicine ,Animals ,Homeostasis ,Humans ,Receptor ,Regulation of gene expression ,Computational Biology ,Prostatic Neoplasms ,Cancer ,medicine.disease ,Hydroxycholesterols ,Cholesterol ,030104 developmental biology ,Endocrinology ,Receptors, LDL ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Cholestanetriol 26-Monooxygenase ,Immunostaining ,Sterol Regulatory Element Binding Protein 2 - Abstract
In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growth in vitro and in tumor xenografts. Studies performed in vitro revealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis. Cancer Res; 77(7); 1662–73. ©2017 AACR.
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- 2017
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44. Proteomic Analysis of Primary Human Airway Epithelial Cells Exposed to the Respiratory Toxicant Diacetyl
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Francine L. Kelly, William M. Gwinn, Scott M. Palmer, David M. Brass, J. Will Thompson, Matthew W. Foster, M. Arthur Moseley, Daniel L. Morgan, and Ashlee M. Valente
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Male ,0301 basic medicine ,Adolescent ,Proteome ,Primary Cell Culture ,Cell Culture Techniques ,Bronchiolitis obliterans ,Diacetyl ,Respiratory Mucosa ,Biology ,Biochemistry ,Article ,Cornified envelope ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Keratin ,medicine ,Humans ,Cilia ,Phosphorylation ,chemistry.chemical_classification ,Keratin-6 ,Cell Differentiation ,Epithelial Cells ,Molecular Sequence Annotation ,General Chemistry ,Middle Aged ,medicine.disease ,Molecular biology ,Epithelium ,Squamous metaplasia ,Flavoring Agents ,Gene Ontology ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,030220 oncology & carcinogenesis ,Respiratory epithelium ,Volatilization ,Toxicant - Abstract
Occupational exposures to the diketone flavoring agent, diacetyl, have been associated with bronchiolitis obliterans, a rare condition of airway fibrosis. Model studies in rodents have suggested that the airway epithelium is a major site of diacetyl toxicity, but the effects of diacetyl exposure upon the human airway epithelium are poorly characterized. Here, we performed quantitative LC-MS/MS-based proteomics to study the effects of repeated diacetyl vapor exposures on three-dimensional organotypic cultures of human primary tracheobronchial epithelial cells. Using a label-free approach, we quantified approximately 3,400 proteins and 5,700 phosphopeptides in cell lysates across four independent donors. Altered expression of proteins and phosphopeptides were suggestive of loss of cilia and increased squamous differentiation in diacetyl-exposed cells. These phenomena were confirmed by immunofluorescence staining of culture cross-sections. Hyperphosphorylation, and crosslinking, of basal cell keratins were also observed in diacetyl-treated cells, and we used parallel reaction monitoring to confidently localize and quantify previously uncharacterized sites of phosphorylation in keratin 6. Collectively, these data identify numerous molecular changes in the epithelium that may be important to the pathogenesis of flavoring-induced bronchiolitis obliterans. More generally, this study highlights the utility of quantitative proteomics for the study of in vitro models of airway injury and disease.
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- 2017
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45. Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-Metabolites in Frozen Human Plasma
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Cian Monnin, Anthony D. Postle, S. J. Kumari A. Ubhayasekera, Matej Orešič, Tomas Cajka, Jacquelyn M. Weir, Candice Z. Ulmer, Stephen E. Somerville, Xueqing Zhao, Therese Koal, Renu Nandakumar, Senlin Zhou, Denis Reynaud, John A. Bowden, James E. Evans, Joost Brandsma, Rhishikesh Thakare, Jeremy P. Koelmel, Houli Jiang, Tuulia Hyötyläinen, Christoph H. Borchers, Oliver Fiehn, J. Will Thompson, Susanne Sales, Karen Lin, Christina M. Jones, Jun Han, Aveline H. Neo, Laila Abdullah, Charles N. Serhan, Mary R. Roth, Danielle J. McDougall, Alexander Triebl, Martin Trötzmüller, Yazen Alnouti, Serge Cremers, Michelle Cinel, Irwin J. Kurland, Kai Schuhmann, Craig E. Wheelock, Min Yuan, Romain A. Colas, Ruth Welti, Yingying Huang, Hiroaki Takeda, Timothy J. Garrett, Jon Rees, Takeshi Bamba, Grielof Koster, Michal A. Surma, Libin Yao, Natalie A. Mellett, Johan Kolmert, M. Arthur Moseley, Krishna Rao Maddipati, Harald Köfeler, John M. Asara, Dajana Vuckovic, Aaron M. Armando, Michael S. Gardner, Peter J. Meikle, Rebecca S. Pugh, Yoshihiro Izumi, Alexander Fauland, Antonio Checa, Jonas Bergquist, Amaury Cazenave-Gassiot, Parsram Ramrup, Zsuzsanna Kuklenyik, Alan Heckert, Hongfeng Jiang, Yunping Qiu, David A. Peake, Oswald Quehenberger, Markus R. Wenk, John R. Barr, Michael Leadley, Linda Ahonen, Barbara Rembiesa, Jiang Jiang, Martin Post, Kristaps Klavins, Susanne B. Breitkopf, Lisa St. John-Williams, Michal L. Schwartzman, Edward A. Dennis, Andrej Shevchenko, Katherine H. Gotlinger, Federico Torta, Christian Klose, Jason S. Pierce, Rainey E. Patterson, Reiko Kiyonami, and Maureen Kachman
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0301 basic medicine ,Biochemistry & Molecular Biology ,Laboratory Proficiency Testing ,International Cooperation ,sterols ,QD415-436 ,Medical Biochemistry and Metabolomics ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Endocrinology ,fatty acyls ,Lipidomics ,Humans ,Ionization mass spectrometry ,quality control ,Reference standards ,phospholipids ,Research Articles ,Observer Variation ,sphingolipids ,Chromatography ,quantitation ,Chemistry ,010401 analytical chemistry ,Standard Reference Material 1950 ,glycerolipids ,ta1182 ,Reproducibility of Results ,Cell Biology ,National Institute of Standards and Technology ,Reference Standards ,Lipid Metabolism ,Lipids ,0104 chemical sciences ,Cell and molecular biology ,Benchmarking ,030104 developmental biology ,Human plasma ,NIST ,Biochemistry and Cell Biology ,Targeted metabolomics - Abstract
As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.
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- 2017
46. Reprioritization of biofilm metabolism is associated with nutrient adaptation and long-term survival of Haemophilus influenzae
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Rachel M. Wallace, Rachael L. Hardison, Derek R. Heimlich, J. Will Thompson, Sheryl S. Justice, Lisa St. John-Williams, M. Arthur Moseley, Peter White, Meghan O’ Bryan, Kevin M. Mason, Laura G. Dubois, James Fitch, Robert Sebra, and Alistair Harrison
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chemistry.chemical_classification ,0303 health sciences ,Glycogen ,030306 microbiology ,Metabolite ,Biofilm ,Phosphodiesterase ,Metabolism ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Microbiology ,lcsh:Microbial ecology ,Haemophilus influenzae ,03 medical and health sciences ,chemistry.chemical_compound ,Metabolic pathway ,Enzyme ,chemistry ,medicine ,lcsh:QR100-130 ,030304 developmental biology ,Biotechnology - Abstract
Nontypeable Haemophilus influenzae (NTHI) is a human-restricted pathogen with an essential requirement for heme–iron acquisition. We previously demonstrated that microevolution of NTHI promotes stationary phase survival in response to transient heme–iron restriction. In this study, we examine the metabolic contributions to biofilm formation using this evolved NTHI strain, RM33. Quantitative analyses identified 29 proteins, 55 transcripts, and 31 metabolites that significantly changed within in vitro biofilms formed by RM33. The synthesis of all enzymes within the tryptophan and glycogen pathways was significantly increased in biofilms formed by RM33 compared with the parental strain. In addition, increases were observed in metabolite transport, adhesin production, and DNA metabolism. Furthermore, we observed pyruvate as a pivotal point in the metabolic pathways associated with changes in cAMP phosphodiesterase activity during biofilm formation. Taken together, changes in central metabolism combined with increased stores of nutrients may serve to counterbalance nutrient sequestration.
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- 2019
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47. International Ring Trial of a High Resolution Targeted Metabolomics and Lipidomics Platform for Serum and Plasma Analysis
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Fuad J. Naser, Jerzy Adamski, Catherine L. Winder, Akos Pal, Kendra J. Adams, David J. Borts, Andreas Huhmer, Jiamin Zheng, John A. Bowden, Therese Koal, David A. Gaul, Donna M. O'Neil, M. Arthur Moseley, Gregory Byram, Gary J. Patti, Karolina Sulek, Hai Pham-Tuan, Florian Meier, Lisa St. John-Williams, Catherine G. Vasilopoulou, Tong Shen, Andrew D. Southam, Facundo M. Fernández, Oliver Fiehn, Yasmin Asad, Lun Zhang, J. Will Thompson, David S. Wishart, Warwick B. Dunn, Stormy L. Koeniger, Viet Dang, Anastasia Kalli, Rupasri Mandal, Cornelia Prehn, Mark R. Viant, and Florence I. Raynaud
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Male ,Analyte ,Biogenic Amines ,Resolution (mass spectrometry) ,Metabolite ,010402 general chemistry ,Orbitrap ,01 natural sciences ,Mass Spectrometry ,Article ,Analytical Chemistry ,law.invention ,chemistry.chemical_compound ,Data Aggregation ,Mice ,Metabolomics ,law ,Limit of Detection ,Lipidomics ,Metabolome ,Animals ,Humans ,Amino Acids ,Chromatography, High Pressure Liquid ,Chromatography ,Analysis of Variance ,010401 analytical chemistry ,Reproducibility of Results ,Lipids ,0104 chemical sciences ,Rats ,chemistry ,High Pressure Liquid ,NIST ,Female ,Other Chemical Sciences ,Blood Chemical Analysis - Abstract
A challenge facing metabolomics in the analysis of large human cohorts is the cross-laboratory comparability of quantitative metabolomics measurements. In this study, 14 laboratories analyzed various blood specimens using a common experimental protocol provided with the Biocrates AbsoluteIDQ p400HR kit, to quantify up to 408 metabolites. The specimens included human plasma and serum from male and female donors, mouse and rat plasma, as well as NIST SRM 1950 reference plasma. The metabolite classes covered range from polar (e.g., amino acids and biogenic amines) to nonpolar (e.g., diacyl- and triacyl-glycerols), and they span 11 common metabolite classes. The manuscript describes a strict system suitability testing (SST) criteria used to evaluate each laboratory's readiness to perform the assay, and provides the SST Skyline documents for public dissemination. The study found approximately 250 metabolites were routinely quantified in the sample types tested, using Orbitrap instruments. Interlaboratory variance for the NIST SRM-1950 has a median of 10% for amino acids, 24% for biogenic amines, 38% for acylcarnitines, 25% for glycerolipids, 23% for glycerophospholipids, 16% for cholesteryl esters, 15% for sphingolipids, and 9% for hexoses. Comparing to consensus values for NIST SRM-1950, nearly 80% of comparable analytes demonstrated bias of
- Published
- 2019
48. Bile acids targeted metabolomics and medication classification data in the ADNI1 and ADNIGO/2 cohorts
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Lisa St. John-Williams, Siamak Mahmoudiandehkordi, Matthias Arnold, Tyler Massaro, Colette Blach, Gabi Kastenmüller, Gregory Louie, Alexandra Kueider-Paisley, Xianlin Han, Rebecca Baillie, Alison A. Motsinger-Reif, Daniel Rotroff, Kwangsik Nho, Andrew J. Saykin, Shannon L. Risacher, Therese Koal, M. Arthur Moseley, Jessica D. Tenenbaum, J. Will Thompson, Rima Kaddurah-Daouk, Alzheimer’s Disease Neuroimaging Initiative, and Alzheimer’s Disease Metabolomics Consortium
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Male ,Statistics and Probability ,Data Descriptor ,Bioinformatics ,MEDLINE ,Disease ,Library and Information Sciences ,Education ,Bile Acids and Salts ,03 medical and health sciences ,0302 clinical medicine ,Metabolomics ,Neuroimaging ,Alzheimer Disease ,Medicine ,Dementia ,Humans ,lcsh:Science ,030304 developmental biology ,Aged ,Aged, 80 and over ,0303 health sciences ,business.industry ,Mechanism (biology) ,Alzheimer's disease ,medicine.disease ,3. Good health ,Computer Science Applications ,Cohort ,Etiology ,Disease Progression ,Female ,lcsh:Q ,Statistics, Probability and Uncertainty ,business ,030217 neurology & neurosurgery ,Information Systems - Abstract
Alzheimer’s disease (AD) is the most common cause of dementia. The mechanism of disease development and progression is not well understood, but increasing evidence suggests multifactorial etiology, with a number of genetic, environmental, and aging-related factors. There is a growing body of evidence that metabolic defects may contribute to this complex disease. To interrogate the relationship between system level metabolites and disease susceptibility and progression, the AD Metabolomics Consortium (ADMC) in partnership with AD Neuroimaging Initiative (ADNI) is creating a comprehensive biochemical database for patients in the ADNI1 cohort. We used the Biocrates Bile Acids platform to evaluate the association of metabolic levels with disease risk and progression. We detail the quantitative metabolomics data generated on the baseline samples from ADNI1 and ADNIGO/2 (370 cognitively normal, 887 mild cognitive impairment, and 305 AD). Similar to our previous reports on ADNI1, we present the tools for data quality control and initial analysis. This data descriptor represents the third in a series of comprehensive metabolomics datasets from the ADMC on the ADNI., Measurement(s)bile acid • MedicationTechnology Type(s)ultra high performance liquid chromatography with mass spectrometer • Resource InformaticsFactor Type(s)age • biological sex • cognitive stateSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.9724652
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- 2019
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49. More sensitivity is always better: Measuring sub-clinical levels of serum thyroglobulin on a µLC-MS/MS system
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Russell P. Grant, Jay S. Johnson, J. Will Thompson, Christopher M. Shuford, Patricia L. Holland, and Andrew N. Hoofnagle
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0303 health sciences ,Recurrent thyroid cancer ,Chromatography ,Chemistry ,medicine.medical_treatment ,030302 biochemistry & molecular biology ,010401 analytical chemistry ,Autoantibody ,Mass spectrometry ,medicine.disease ,01 natural sciences ,Lower limit ,Serum thyroglobulin ,Article ,0104 chemical sciences ,03 medical and health sciences ,Sub clinical ,medicine ,Thyroglobulin ,Thyroid cancer ,Spectroscopy - Abstract
Although liquid chromatography–tandem mass spectrometry (LC–MS/MS) assays for thyroglobulin (Tg) are resistant to autoantibody (TgAb) interference, recent studies have demonstrated approximately 40% of TgAb-positive individuals with recurrent thyroid cancer have Tg concentrations below the lower limit of quantification (LLOQ) of the LC–MS/MS assays described to date (i.e.
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- 2019
50. Alzheimer's Risk Factors Age, APOE Genotype, and Sex Drive Distinct Molecular Pathways
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Yingxue Ren, Zonghua Li, Alexandra Kueider-Paisley, Yu Yamazaki, Olivia N. Attrebi, Rima Kaddurah-Daouk, Fuyao Li, Yuka A. Martens, Takahisa Kanekiyo, Akari Yamazaki, Lucy Job, Nilufer Ertekin-Taner, Matthias Arnold, Ligia I. Bastea, Tomonori Aikawa, Siamak MahmoudianDehkordi, Kai Chen, Lisa St. John-Williams, Na Zhao, Francis Shue, Berkiye Sonoustoun, Axel D. Meneses, Guojun Bu, Wenhui Qiao, J. Will Thompson, Peter Storz, Lindsey M. Felton, Jiaying Zheng, Hiroshi Oue, Masaya Tachibana, Chia Chen Liu, and Yan W. Asmann
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0301 basic medicine ,Apolipoprotein E ,Male ,Aging ,Genotype ,Apolipoprotein E2 ,Apolipoprotein E4 ,Apolipoprotein E3 ,Gene Expression ,Mice, Transgenic ,Disease ,Biology ,Article ,Transcriptome ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Apolipoproteins E ,Sex Factors ,Downregulation and upregulation ,Alzheimer Disease ,Risk Factors ,Metabolome ,Animals ,Humans ,Gene Regulatory Networks ,Receptors, Immunologic ,Gene ,Serpins ,Adaptor Proteins, Signal Transducing ,Genetics ,Membrane Glycoproteins ,TREM2 ,General Neuroscience ,Gene Expression Profiling ,Age Factors ,Brain ,Membrane Proteins ,Protective Factors ,030104 developmental biology ,Unfolded Protein Response ,Female ,030217 neurology & neurosurgery - Abstract
Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.
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- 2019
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