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Publication Record


Examining How the MAFB Transcription Factor Affects Islet β-Cell Function Postnatally.
Cyphert HA, Walker EM, Hang Y, Dhawan S, Haliyur R, Bonatakis L, Avrahami D, Brissova M, Kaestner KH, Bhushan A, Powers AC, Stein R
(2019) Diabetes 68: 337-348
MeSH Terms: Animals, Cells, Cultured, Chromatin Immunoprecipitation, Chromosomes, Artificial, Bacterial, DNA Methylation, Female, Humans, In Vitro Techniques, Insulin-Secreting Cells, Maf Transcription Factors, Large, MafB Transcription Factor, Mice, Mice, Transgenic, Pregnancy, Tryptophan Hydroxylase
Show Abstract · Added January 8, 2019
The sustained expression of the MAFB transcription factor in human islet β-cells represents a distinct difference in mice. Moreover, mRNA expression of closely related and islet β-cell-enriched MAFA does not peak in humans until after 9 years of age. We show that the MAFA protein also is weakly produced within the juvenile human islet β-cell population and that expression is postnatally restricted in mouse β-cells by de novo DNA methylation. To gain insight into how MAFB affects human β-cells, we developed a mouse model to ectopically express in adult mouse β-cells using transcriptional control sequences. Coexpression of MafB with MafA had no overt impact on mouse β-cells, suggesting that the human adult β-cell MAFA/MAFB heterodimer is functionally equivalent to the mouse MafA homodimer. However, MafB alone was unable to rescue the islet β-cell defects in a mouse mutant lacking MafA in β-cells. Of note, transgenic production of MafB in β-cells elevated tryptophan hydroxylase 1 mRNA production during pregnancy, which drives the serotonin biosynthesis critical for adaptive maternal β-cell responses. Together, these studies provide novel insight into the role of MAFB in human islet β-cells.
© 2018 by the American Diabetes Association.
1 Communities
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15 MeSH Terms
Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations.
Midttun Ø, Theofylaktopoulou D, McCann A, Fanidi A, Muller DC, Meyer K, Ulvik A, Zheng W, Shu XO, Xiang YB, Prentice R, Thomson CA, Pettinger M, Giles GG, Hodge A, Cai Q, Blot WJ, Wu J, Johansson M, Hultdin J, Grankvist K, Stevens VL, McCullough ML, Weinstein SJ, Albanes D, Langhammer A, Hveem K, Næss M, Sesso HD, Gaziano JM, Buring JE, Lee IM, Severi G, Zhang X, Han J, Stampfer MJ, Smith-Warner SA, Zeleniuch-Jacquotte A, le Marchand L, Yuan JM, Butler LM, Koh WP, Wang R, Gao YT, Ericson U, Sonestedt E, Ziegler RG, Freedman ND, Visvanathan K, Jones MR, Relton C, Brennan P, Johansson M, Ueland PM
(2017) Am J Clin Nutr 105: 1314-1326
MeSH Terms: Aged, Asia, Australia, Biomarkers, Carbon, Cross-Sectional Studies, Dietary Supplements, Female, Humans, Kynurenine, Laboratories, Male, Middle Aged, Scandinavian and Nordic Countries, Tryptophan, United States, Vitamin A, Vitamin B Complex, Vitamin D, alpha-Tocopherol
Show Abstract · Added April 21, 2017
Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies. We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions. The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory. Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all- retinol, 25-hydroxyvitamin D, and α-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users. The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.
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20 MeSH Terms
Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells.
Banerjee RR, Cyphert HA, Walker EM, Chakravarthy H, Peiris H, Gu X, Liu Y, Conrad E, Goodrich L, Stein RW, Kim SK
(2016) Diabetes 65: 2331-41
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Cyclin A2, Cyclin B1, Cyclin B2, Cyclin D1, Cyclin D2, Diabetes, Gestational, Female, Forkhead Box Protein M1, Insulin, Insulin-Secreting Cells, MafB Transcription Factor, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pregnancy, Receptors, Prolactin, Serotonin, Signal Transduction, Tryptophan Hydroxylase
Show Abstract · Added September 19, 2016
β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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23 MeSH Terms
Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions.
Zhang LS, Davies SS
(2016) Genome Med 8: 46
MeSH Terms: Animals, Diet, Disease Susceptibility, Energy Metabolism, Fatty Acids, Volatile, Gastrointestinal Microbiome, Gastrointestinal Tract, Homeostasis, Humans, Indoles, Metabolome, Metabolomics, Methylamines, Microbiota, Translational Medical Research, Tryptophan, Tyrosine
Show Abstract · Added May 6, 2016
Mass spectrometry- and nuclear magnetic resonance-based metabolomic studies comparing diseased versus healthy individuals have shown that microbial metabolites are often the compounds most markedly altered in the disease state. Recent studies suggest that several of these metabolites that derive from microbial transformation of dietary components have significant effects on physiological processes such as gut and immune homeostasis, energy metabolism, vascular function, and neurological behavior. Here, we review several of the most intriguing diet-dependent metabolites that may impact host physiology and may therefore be appropriate targets for therapeutic interventions, such as short-chain fatty acids, trimethylamine N-oxide, tryptophan and tyrosine derivatives, and oxidized fatty acids. Such interventions will require modulating either bacterial species or the bacterial biosynthetic enzymes required to produce these metabolites, so we briefly describe the current understanding of the bacterial and enzymatic pathways involved in their biosynthesis and summarize their molecular mechanisms of action. We then discuss in more detail the impact of these metabolites on health and disease, and review current strategies to modulate levels of these metabolites to promote human health. We also suggest future studies that are needed to realize the full therapeutic potential of targeting the gut microbiota.
2 Communities
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17 MeSH Terms
Effects of acute tryptophan depletion on raphé functional connectivity in depression.
Weinstein JJ, Rogers BP, Taylor WD, Boyd BD, Cowan RL, Shelton KM, Salomon RM
(2015) Psychiatry Res 234: 164-71
MeSH Terms: Adult, Depressive Disorder, Major, Female, Gyrus Cinguli, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Nerve Net, Raphe Nuclei, Thalamus, Tryptophan
Show Abstract · Added February 4, 2016
Depression remains a great societal burden and a major treatment challenge. Most antidepressant medications target serotonergic raphé nuclei. Acute tryptophan depletion (ATD) modulates serotonin function. To better understand the raphé's role in mood networks, we studied raphé functional connectivity in depression. Fifteen depressed patients were treated with sertraline for 12 weeks and scanned during ATD and sham conditions. Based on our previous findings in a separate cohort, resting state MRI functional connectivity between raphé and other depression-related regions (ROIs) was analyzed in narrow frequency bands. ATD decreased raphé functional connectivity with the bilateral thalamus within 0.025-0.05 Hz, and also decreased raphé functional connectivity with the right pregenual anterior cingulate cortex within 0.05-0.1 Hz. Using the control broadband filter 0.01-0.1 Hz, no significant differences in raphé-ROI functional connectivity were observed. Post-hoc analysis by remission status suggested increased raphé functional connectivity with left pregenual anterior cingulate cortex in remitters (n=10) and decreased raphé functional connectivity with left thalamus in non-remitters (n=5), both within 0.025-0.05 Hz. Reducing serotonin function appears to alter coordination of these mood-related networks in specific, low frequency ranges. For examination of effects of reduced serotonin function on mood-related networks, specific low frequency BOLD fMRI signals can identify regions implicated in neural circuitry and may enable clinically-relevant interpretation of functional connectivity measures. The biological significance of these low frequency signals detected in the raphé merits further study.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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12 MeSH Terms
Immunomodulatory metabolites released by the frog-killing fungus Batrachochytrium dendrobatidis.
Rollins-Smith LA, Fites JS, Reinert LK, Shiakolas AR, Umile TP, Minbiole KP
(2015) Infect Immun 83: 4565-70
MeSH Terms: Adenosine, Animals, Apoptosis, Cell Survival, Chytridiomycota, Drug Synergism, Host-Pathogen Interactions, Humans, Jurkat Cells, Kynurenine, Lymphocytes, Mycoses, Skin, Thionucleosides, Tryptophan, Xenopus laevis
Show Abstract · Added April 18, 2017
Batrachochytrium dendrobatidis is a fungal pathogen in the phylum Chytridiomycota that causes the skin disease chytridiomycosis. Chytridiomycosis is considered an emerging infectious disease linked to worldwide amphibian declines and extinctions. Although amphibians have well-developed immune defenses, clearance of this pathogen from the skin is often impaired. Previously, we showed that the adaptive immune system is involved in the control of the pathogen, but B. dendrobatidis releases factors that inhibit in vitro and in vivo lymphocyte responses and induce lymphocyte apoptosis. Little is known about the nature of the inhibitory factors released by this fungus. Here, we describe the isolation and characterization of three fungal metabolites produced by B. dendrobatidis but not by the closely related nonpathogenic chytrid Homolaphlyctis polyrhiza. These metabolites are methylthioadenosine (MTA), tryptophan, and an oxidized product of tryptophan, kynurenine (Kyn). Independently, both MTA and Kyn inhibit the survival and proliferation of amphibian lymphocytes and the Jurkat human T cell leukemia cell line. However, working together, they become effective at much lower concentrations. We hypothesize that B. dendrobatidis can adapt its metabolism to release products that alter the local environment in the skin to inhibit immunity and enhance the survival of the pathogen.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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16 MeSH Terms
Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression.
Brouwers B, de Faudeur G, Osipovich AB, Goyvaerts L, Lemaire K, Boesmans L, Cauwelier EJ, Granvik M, Pruniau VP, Van Lommel L, Van Schoors J, Stancill JS, Smolders I, Goffin V, Binart N, in't Veld P, Declercq J, Magnuson MA, Creemers JW, Schuit F, Schraenen A
(2014) Cell Metab 20: 979-90
MeSH Terms: Animals, Female, Human Growth Hormone, Humans, Islets of Langerhans, Male, Mice, Mice, Transgenic, Receptors, Prolactin, Tryptophan Hydroxylase
Show Abstract · Added December 11, 2014
The human growth hormone (hGH) minigene is frequently used in the derivation of transgenic mouse lines to enhance transgene expression. Although this minigene is present in the transgenes as a secondcistron, and thus not thought to be expressed, we found that three commonly used lines, Pdx1-Cre(Late), RIP-Cre, and MIP-GFP, each expressed significant amounts of hGH in pancreatic islets. Locally secreted hGH binds to prolactin receptors on β cells, activates STAT5 signaling, and induces pregnancy-like changes in gene expression, thereby augmenting pancreatic β cell mass and insulin content. In addition, islets of Pdx1-Cre(Late) mice have lower GLUT2 expression and reduced glucose-induced insulin release and are protected against the β cell toxin streptozotocin. These findings may be important when interpreting results obtained when these and other hGH minigene-containing transgenic mice are used.
Copyright © 2014 Elsevier Inc. All rights reserved.
2 Communities
2 Members
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10 MeSH Terms
Tyrosine/cysteine cluster sensitizing human γD-crystallin to ultraviolet radiation-induced photoaggregation in vitro.
Schafheimer N, Wang Z, Schey K, King J
(2014) Biochemistry 53: 979-90
MeSH Terms: Amino Acid Substitution, Cataract, Cysteine, Humans, Lens, Crystalline, Protein Denaturation, Protein Folding, Protein Structure, Quaternary, Tryptophan, Tyrosine, Ultraviolet Rays, gamma-Crystallins
Show Abstract · Added May 27, 2014
Ultraviolet radiation (UVR) exposure is a major risk factor for age-related cataract, a protein-aggregation disease of the human lens often involving the major proteins of the lens, the crystallins. γD-Crystallin (HγD-Crys) is abundant in the nucleus of the human lens, and its folding and aggregation have been extensively studied. Previous work showed that HγD-Crys photoaggregates in vitro upon exposure to UVA/UVB light and that its conserved tryptophans are not required for aggregation. Surprisingly, the tryptophan residues play a photoprotective role because of a distinctive energy-transfer mechanism. HγD-Crys also contains 14 tyrosine residues, 12 of which are organized as six pairs. We investigated the role of the tyrosines of HγD-Crys by replacing pairs with alanines and monitoring photoaggregation using light scattering and SDS-PAGE. Mutating both tyrosines in the Y16/Y28 pair to alanine slowed the formation of light-scattering aggregates. Further mutant studies implicated Y16 as important for photoaggregation. Mass spectrometry revealed that C18, in contact with Y16, is heavily oxidized during UVR exposure. Analysis of multiple mutant proteins by mass spectrometry suggested that Y16 and C18 likely participate in the same photochemical process. The data suggest an initial photoaggregation pathway for HγD-Crys in which excited-state Y16 interacts with C18, initiating radical polymerization.
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12 MeSH Terms
A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin.
Xu R, Krause JC, McBride R, Paulson JC, Crowe JE, Wilson IA
(2013) Nat Struct Mol Biol 20: 363-70
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Antibodies, Neutralizing, Antibodies, Viral, Antigen-Antibody Complex, Binding Sites, Crystallography, X-Ray, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Humans, Immunoglobulin Fab Fragments, Influenza A Virus, H2N2 Subtype, Molecular Sequence Data, Mutation, Protein Conformation, Tryptophan, Tyrosine
Show Abstract · Added January 26, 2016
Influenza virus hemagglutinin (HA) mediates receptor binding and viral entry during influenza infection. The development of receptor analogs as viral-entry blockers has not been successful, which suggests that sialic acid may not be an ideal scaffold to obtain broad, potent HA inhibitors. Here, we report crystal structures of Fab fragments from three human antibodies that neutralize the 1957 pandemic H2N2 influenza virus in complex with H2 HA. All three antibodies use an aromatic residue to plug a conserved cavity in the HA receptor-binding site. Each antibody interacts with the absolutely conserved HA1 Trp153 at the cavity base through π-π stacking with the signature Phe54 of two VH1-69-encoded antibodies or a tyrosine from HCDR3 in the other antibody. This highly conserved interaction can be used as a starting point to design inhibitors targeting this conserved hydrophobic pocket in influenza viruses.
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17 MeSH Terms
The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness*.
Adams Wilson JR, Morandi A, Girard TD, Thompson JL, Boomershine CS, Shintani AK, Ely EW, Pandharipande PP
(2012) Crit Care Med 40: 835-41
MeSH Terms: Acute Disease, Aged, Brain Diseases, Critical Illness, Female, Humans, Kynurenine, Male, Metabolic Networks and Pathways, Middle Aged, Prospective Studies, Tryptophan
Show Abstract · Added September 23, 2015
OBJECTIVES - Plasma tryptophan levels are associated with delirium in critically ill patients. Although tryptophan has been linked to the pathogenesis of other neurocognitive diseases through metabolism to neurotoxins via the kynurenine pathway, a role for kynurenine pathway activity in intensive care unit brain dysfunction (delirium and coma) remains unknown. This study examined the association between kynurenine pathway activity as determined by plasma kynurenine concentrations and kynurenine/tryptophan ratios and presence or absence of acute brain dysfunction (defined as delirium/coma-free days) in intensive care unit patients.
DESIGN, SETTING, AND PATIENTS - This was a prospective cohort study that utilized patient data and blood samples from the Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction trial, which compared sedation with dexmedetomidine vs. lorazepam in mechanically ventilated patients.
MEASUREMENTS AND MAIN RESULTS - Baseline plasma kynurenine and tryptophan concentrations were measured using high-performance liquid chromatography with or without tandem mass spectrometry. Delirium was assessed daily using the Confusion Assessment Method for the Intensive Care Unit. Linear regression examined associations between kynurenine pathway activity and delirium/coma-free days after adjusting for sedative exposure, age, and severity of illness. Among 84 patients studied, median age was 60 yrs and Acute Physiology and Chronic Health Evaluation II score was 28.5. Elevated plasma kynurenine and kynurenine/tryptophan ratio were both independently associated with significantly fewer delirium/coma-free days (i.e., fewer days without acute brain dysfunction). Specifically, patients with plasma kynurenine or kynurenine/tryptophan ratios at the 75th percentile of our population had an average of 1.8 (95% confidence interval 0.6-3.1) and 2.1 (95% confidence interval 1.0-3.2) fewer delirium/coma-free days than those patients with values at the 25th percentile (p = .006 and p < .001, respectively).
CONCLUSIONS - Increased kynurenine pathway activation, assessed by plasma kynurenine and kynurenine/tryptophan ratio, was associated with fewer days alive and without acute brain dysfunction in intensive care unit patients. Future studies are warranted to clarify this relationship and investigate potential therapeutic interventions.
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12 MeSH Terms