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Work 1-10 of 68

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Article

The Polyadenosine RNA-binding Protein, Zinc Finger Cys(3)His Protein 14 (ZC3H14), Regulates the Pre-mRNA Processing of a Key ATP Synthase Subunit mRNA

by Callie P. Wigington; Kevin J. Morris; Laura E. Newman; Anita Corbett

2016

Subjects
  • Chemistry, Biochemistry
  • Biology, Cell
  • File Download
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Abstract:Close

Polyadenosine RNA-binding proteins (Pabs) regulate multiple steps in gene expression. This protein family includes the well studied Pabs, PABPN1 and PABPC1, as well as the newly characterized Pab, zinc finger CCCH-type containing protein 14 (ZC3H14). Mutations in ZC3H14 are linked to a form of intellectual disability. To probe the function of ZC3H14, we performed a transcriptome-wide analysis of cells depleted of either ZC3H14 or the control Pab, PABPN1. Depletion of PABPN1 affected - 17% of expressed transcripts, whereas ZC3H14 affected only - 1% of expressed transcripts. To assess the function of ZC3H14 in modulating target mRNAs, we selected the gene encoding the ATP synthase F 0 subunit C (ATP5G1) transcript. Knockdown of ZC3H14 significantly reduced ATP5G1 steady-state mRNA levels. Consistent with results suggesting that ATP5G1 turnover increases upon depletion of ZC3H14, double knockdown of ZC3H14 and the nonsense-mediated decay factor, UPF1, rescues ATP5G1 transcript levels. Furthermore, fractionation reveals an increase in the amount of ATP5G1 pre-mRNA that reaches the cytoplasm when ZC3H14 is depleted and that ZC3H14 binds to ATP5G1 pre-mRNA in the nucleus. These data support a role for ZC3H14 in ensuring proper nuclear processing and retention of ATP5G1 pre-mRNA. Consistent with the observation that ATP5G1 is a rate-limiting component for ATP synthase activity, knockdown of ZC3H14 decreases cellular ATP levels and causes mitochondrial fragmentation. These data suggest that ZC3H14 modulates pre-mRNA processing of select mRNA transcripts and plays a critical role in regulating cellular energy levels, observations that have broad implications for proper neuronal function.

Article

The functional serotonin 1a receptor promoter polymorphism, rs6295, is associated with psychiatric illness and differences in transcription

by ZR Donaldson; B le Francois; TL Santos; Lynn Almli; M Boldrini; FA Champagne; V Arango; JJ Mann; CA Stockmeier; H Galfalvy; PR Albert; Kerry Ressler; R Hen

2016

Subjects
  • Biology, Genetics
  • Health Sciences, Mental Health
  • Psychology, Psychobiology
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Abstract:Close

The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological mechanism underlying the association between rs6295, trauma and mental illness. Moreover, our results suggest that rs6295 may affect transcription during both gestational development and adulthood in a region-specific manner, acting as a risk factor for psychiatric illness. These findings provide a critical framework for conceptualizing the effects of a common functional genetic variant, trauma exposure and their impact on mental health.

Article

Presentation of hepatocellular antigens

by Arash Grakoui; Ian Nicholas Crispe

2016

Subjects
  • Health Sciences, Immunology
  • Health Sciences, Pathology
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The liver is an organ in which antigen-specific T-cell responses manifest a bias toward immune tolerance. This is clearly seen in the rejection of allogeneic liver transplants, and multiple other phenomena suggest that this effect is more general. These include tolerance toward antigens introduced via the portal vein, immune failure to several hepatotropic viruses, the lack of natural liver-stage immunity to malaria parasites, and the frequent metastasis of cancers to the liver. Here we review the mechanisms by which T cells engage with hepatocellular antigens, the context in which such encounters occur, and the mechanisms that act to suppress a full T-cell response. While many mechanisms play a role, we will argue that two important processes are the constraints on the cross-presentation of hepatocellular antigens, and the induction of negative feedback inhibition driven by interferons. The constant exposure of the liver to microbial products from the intestine may drive innate immunity, rendering the local environment unfavorable for specific T-cell responses through this mechanism. Nevertheless, tolerance toward hepatocellular antigens is not monolithic and under specific circumstances allows both effective immunity and immunopathology.

Article

Increased risk of latent tuberculous infection among persons with pre-diabetes and diabetes mellitus

by R. L. Hensel; Russell Kempker; J. Tapia; A. Oladele; Henry Blumberg; Matthew Magee

2016

Subjects
  • Health Sciences, Epidemiology
  • Health Sciences, Public Health
  • Biology, Biostatistics
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Abstract:Close

SETTING: Although diabetes mellitus (DM) is an established risk factor for active tuberculosis (TB) disease, little is known about the association between pre-DM, DM, and latent tuberculous infection (LTBI). OBJECTIVE: To estimate the association between DM and LTBI. DESIGN: We conducted a cross-sectional study among recently arrived refugees seen at a health clinic in Atlanta, GA, USA, between 2013 and 2014. Patients were screened for DM using glycosylated-hemoglobin (HbA1c), and for LTBI using the QuantiFERONw-TB (QFT) test. HbA1c and QFT results, demographic information, and medical history were abstracted from patient charts. RESULTS: Among 702 included patients, 681 (97.0%) had HbA1c and QFT results. Overall, 54 (7.8%) patients had DM and 235 (33.8%) had pre-DM. LTBI was prevalent in 31.3% of the refugees. LTBI prevalence was significantly higher (P < 0.01) among patients with DM (43.4%) and pre-DM (39.1%) than in those without DM (25.9%). Refugees with DM (adjusted OR [aOR] 2.3, 95%CI 1.2-4.5) and pre-DM (aOR 1.7, 95%CI 1.1-2.4) were more likely to have LTBI than those without DM. CONCLUSION: Refugees with DM or pre-DM from high TB burden countries were more likely to have LTBI than those without DM. Dysglycemia may impair the immune defenses involved in preventing Mycobacterium tuberculosis infection.

Article

Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

by Cordelia Manickam; Premeela Rajakumar; Lynn Wachtman; Joshua A. Kramer; Amanda J. Martinot; Valerie Varner; Luis D. Giavedoni; R. Keith Reeves

2016

Subjects
  • Health Sciences, Immunology
  • Biology, Virology
  • Biology, Cell
  • File Download
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Abstract:Close

Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R = 0.698; P = 0.015) and liver (R = 0.567; P = 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-γ) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection.

Article

Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder

by David Goldsmith; Ebrahim Haroon; Bobbi J. Woolwine; Moon Y. Jung; Evanthia C. Wommack; Philip D. Harvey; Michael Treadway; Jennifer Felger; Andrew Miller

2016

Subjects
  • Psychology, Behavioral
  • Health Sciences, Oncology
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Abstract:Close

Previous data have demonstrated that administration of inflammatory cytokines or their inducers leads to altered basal ganglia function associated with reduced psychomotor speed. Decreased psychomotor speed, referred to clinically as psychomotor retardation, is a cardinal symptom of major depressive disorder (MDD) and has been associated with poor antidepressant treatment response. We therefore examined the association between plasma inflammatory markers and psychomotor speed in ninety-three un-medicated patients with MDD. Psychomotor speed was assessed by a range of neuropsychological tests from purely motor tasks (e.g. movement latency and finger tapping) to those that involved motor activity with increasing cognitive demand and cortical participation (e.g. Trails A and Digit Symbol Substitution Task (DSST)). Linear regression analyses were performed to determine the relationship of inflammatory markers and psychomotor task performance controlling for age, race, sex, education, body mass index, and severity of depression. MDD patients exhibited decreased psychomotor speed on all tasks relative to normative standards. Increased IL-6 was associated with decreased performance on simple and choice movement time tasks, whereas MCP-1 was associated with decreased performance on the finger tapping task and DSST. IL-10 was associated with increased performance on the DSST. In an exploratory principle component analysis including all psychomotor tasks, IL-6 was associated with the psychomotor speed factor. Taken together, the data indicate that a peripheral inflammatory profile including increased IL-6 and MCP-1 is consistently associated with psychomotor speed in MDD. These data are consistent with data demonstrating that inflammation can affect basal ganglia function, and indicate that psychomotor speed may be a viable outcome variable for anti-inflammatory therapies in depression and other neuropsychiatric disorders with increased inflammation.

Article

N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection

by Nandan S. Gokhale; Alexa B.R. McIntyre; Michael J. McFadden; Allison E. Roder; Edward M. Kennedy; Jorge A. Gandara; Sharon E. Hopcraft; Kendra M. Quicke; Christine Vazquez; Jason Willer; Olga R. Ilkayeva; Brittany A. Law; Christopher L. Holley; Mariano A. Garcia-Blanco; Matthew J. Evans; Mehul Suthar; Shelton S. Bradrick; Christopher E. Mason; Stacy M. Horner

2016

Subjects
  • Biology, Microbiology
  • Biology, Genetics
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Abstract:Close

The RNA modification N6-methyladenosine (m6A) post-transcriptionally regulates RNA function. The cellular machinery that controls m6A includes methyltransferases and demethylases that add or remove this modification, as well as m6A-binding YTHDF proteins that promote the translation or degradation of m6A-modified mRNA. We demonstrate that m6A modulates infection by hepatitis C virus (HCV). Depletion of m6A methyltransferases or an m6A demethylase, respectively, increases or decreases infectious HCV particle production. During HCV infection, YTHDF proteins relocalize to lipid droplets, sites of viral assembly, and their depletion increases infectious viral particles. We further mapped m6A sites across the HCV genome and determined that inactivating m6A in one viral genomic region increases viral titer without affecting RNA replication. Additional mapping of m6A on the RNA genomes of other Flaviviridae, including dengue, Zika, yellow fever, and West Nile virus, identifies conserved regions modified by m6A. Altogether, this work identifies m6A as a conserved regulatory mark across Flaviviridae genomes.

Article

Bacterial Density, Serotype Distribution and Antibiotic Resistance of Pneumococcal Strains from the Nasopharynx of Peruvian Children Before and After Pneumococcal Conjugate Vaccine 7

by Carla Berg; Christiane R. Hanke; Carlos G. Grijalva; Sopio Chochua; Mathias W. Pletz; Claudia Hornberg; Kathryn M. Edwards; Marie R. Griffin; Hector Verastegui; Ana I. Gil; Claudio F. Lanata; Keith Klugman; Jorge Vidal Graniel

2016

Subjects
  • Health Sciences, Public Health
  • File Download
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Background: Pneumococcal conjugate vaccines (PCV) have decreased nasopharyngeal carriage of vaccine types but little data exist from rural areas. We investigated bacterial density, serotype distribution and antibiotic resistance of pneumococcal strains within the nasopharynx of young children in the Peruvian Andes, 2 years after PCV7 was introduced. Methods: Pneumococcal strains were isolated from a subset of 125 children from our Peruvian cohort, who entered the study in 2009 and had pneumococcus detected in the nasopharynx in both 2009 and during follow-up in 2011. Strains were Quellung-serotyped and tested for susceptibility to antibiotics. Bacterial density was determined by quantitative polymerase chain reaction. Results: The prevalence of PCV7 strains decreased from 48% in 2009 to 28.8% in 2011, whereas non-PCV7 types increased from 52% to 71.2% (P = 0.002). There was a 3.5-fold increase in carriage of serotype 6C in 2011 (P = 0.026). Vaccination with PCV7 did not affect pneumococcal density in children colonized by a PCV7 type but did increase density in those colonized with a non-PCV7 type. Antibiotic resistance did not change after vaccine introduction; strains were nonsusceptible to tetracycline (97.2%), trimethoprim-sulfamethoxazole (56.4%), penicillin (34%), erythromycin (22.4%), chloramphenicol (18.8%) and clindamycin (12.4%). Conclusions: Serotype replacement was observed post-PCV7 vaccination with a concomitant, not previously recognized, increased nasopharyngeal density.

Article

Associations of place characteristics with HIV and HCV risk behaviors among racial/ethnic groups of people who inject drugs in the United States

by Sabriya Linton; Hannah Cooper; Mary Kelley; Conny C. Karnes; Zev Ross; Mary E. Wolfe; Yen-Tyng Chen; Samuel R. Friedman; Don Des Jarlais; Salaam Semaan; Barbara Tempalski; Catlainn Sionean; Elizabeth DiNenno; Cyprian Wejnert; Gabriella Paz-Bailey

2016

Subjects
  • Health Sciences, Public Health
  • Health Sciences, Epidemiology
  • Biology, Virology
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Purpose Investigate whether characteristics of geographic areas are associated with condomless sex and injection-related risk behavior among racial/ethnic groups of people who inject drugs (PWID) in the United States. Methods PWID were recruited from 19 metropolitan statistical areas for 2009 National HIV Behavioral Surveillance. Administrative data described ZIP codes, counties, and metropolitan statistical areas where PWID lived. Multilevel models, stratified by racial/ethnic groups, were used to assess relationships of place-based characteristics to condomless sex and injection-related risk behavior (sharing injection equipment). Results Among black PWID, living in the South (vs. Northeast) was associated with injection-related risk behavior (adjusted odds ratio [AOR] = 2.24, 95% confidence interval [CI]  = 1.21–4.17; P =.011), and living in counties with higher percentages of unaffordable rental housing was associated with condomless sex (AOR = 1.02, 95% CI = 1.00–1.04; P =.046). Among white PWID, living in ZIP codes with greater access to drug treatment was negatively associated with condomless sex (AOR = 0.93, 95% CI = 0.88–1.00; P =.038). Conclusions Policies that increase access to affordable housing and drug treatment may make environments more conducive to safe sexual behaviors among black and white PWID. Future research designed to longitudinally explore the association between residence in the south and injection-related risk behavior might identify specific place-based features that sustain patterns of injection-related risk behavior.

Article

Serum Endotoxins and Flagellin and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort

by So Yeon Kong; Hao Quang Tran; Andrew Gewirtz; Gail McKeown-Eyssen; Veronika Fedirko; Isabelle Romieu; Anne Tjonneland; Anja Olsen; Kim Overvad; Marie-Christine Boutron-Ruault; Nadia Bastide; Aurelie Affret; Tilman Kuhn ; Rudolf Kaaks; Heiner Boeing; Krasimira Aleksandrova; Antonia Trichipoulou; Maria Kritikou; Effie Vasilopoulou; Domenico Palli; Vittorio Krogh; Amalia Mattiello; Rosario Tumino; Alessio Naccarati; H. Bas Bueno-de-Mesquita; Petra H. Peeters; Elisabete Weiderpass; J. Ramon Quiros; Nuria Sala; Maria-Jose Sanchez; Jose Maria Huerta Castano; Aurelio Barricarte; Miren Dorronsoro; Marten Werner ; Nicholas J. Wareham; Kay-Tee Khaw; Kathryn E. Bradbury; Heinz Freisling; Faidra Stavropoulou; Pietro Ferrari; Marc J. Gunter; Amanda J. Cross ; Elio Riboli; W. Robert Bruce; Mazda Jenab

2016

Subjects
  • Health Sciences, Oncology
  • Health Sciences, Nutrition
  • Health Sciences, Public Health
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Background: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk. Methods: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors. Results: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti- LPS flagellin, 1.66; 95% CI, 1.10-2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47- 1.02; Ptrend, 0.18). Conclusion: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist. Impact: Further studies are warranted to better clarify these preliminary observations.
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