Vitamin A deficiency (VAD) is an important contributor to child morbidity and mortality. The prevalence of VAD, measured by retinol-binding protein (RBP) or retinol, is overestimated in populations with a high prevalence of inflammation. We aimed to quantify and adjust for the effect of inflammation on VAD prevalence in a nationally representative survey of Liberian children 6 to 35months of age. We compared five approaches to adjust RBP for inflammation and estimate VAD prevalence (defined as RBP<0.7μmol/L): (1) ignoring inflammation; (2) excluding individuals with inflammation (C-reactive protein (CRP) >5mg/L or alpha1-acid glycoprotein (AGP) >1g/)L; (3) multiplying each individual's RBP by an internal correction factor; (4) by an external correction factor; and (5) using regression (corrected RBP=exp(InRBP - β1(lnCRPobs-lnCRPref) - β2(lnAGPobs-lnAGPref)). Corrected RBP was based on a regression model where reference lnCRP and lnAGP were set to the maximum of the lowest decile. The unadjusted prevalence of VAD was 24.7%. Children with elevated CRP and/or AGP had significantly lower RBP concentrations than their apparently healthy peers (geometric mean RBP 0.79μmol/L (95% CI: 0.76, 0.82) vs. 0.95μmol/L (95% CI: 0.92, 0.97), P<0.001). Using approaches 2-5 resulted in a prevalence of VAD of 11.6%, 14.3%, 13.5% and 7.3%, respectively. Depending on the approach, the VAD prevalence is reduced 10-17 percentage points when inflammation is taken into account. Further quantification of the influence of inflammation on biomarkers of vitamin A status from other national surveys is needed to compare and recommend the preferred adjustment approach across populations.
by
Lu Xu;
Hongyu Guo;
Christopher M. Boyd;
Mitchel Klein;
Aikaterini Bougiatioti;
Kate M. Cerully;
James R. Hite;
Gabriel Isaacman-VanWertz;
Nathan M. Kreisberg;
Christoph Knote;
Kevin Olson;
Abigail Koss;
Allen H. Goldstein;
Susanne V. Hering;
Joost de Gouw;
Karsten Baumann;
Shan-Hu Lee;
Athanasios Nenes;
Rodney J. Weber;
Nga Lee Ng
Secondary organic aerosol (SOA) constitutes a substantial fraction of fine particulate matter and has important impacts on climate and human health. The extent to which human activities alter SOA formation from biogenic emissions in the atmosphere is largely undetermined. Here, we present direct observational evidence on the magnitude of anthropogenic influence on biogenic SOA formation based on comprehensive ambient measurements in the southeastern United States (US). Multiple high-time-resolution mass spectrometry organic aerosol measurements were made during different seasons at various locations, including urban and rural sites in the greater Atlanta area and Centreville in rural Alabama. Our results provide a quantitative understanding of the roles of anthropogenic SO2 and NOx in ambient SOA formation. We show that isoprene-derived SOA is directly mediated by the abundance of sulfate, instead of the particle water content and/or particle acidity as suggested by prior laboratory studies. Anthropogenic NOx is shown to enhance nighttime SOA formation via nitrate radical oxidation of monoterpenes, resulting in the formation of condensable organic nitrates. Together, anthropogenic sulfate and NOx can mediate 43-70% of total measured organic aerosol (29-49% of submicron particulate matter, PM1) in the southeastern US during summer. These measurements imply that future reduction in SO2 and NOx emissions can considerably reduce the SOA burden in the southeastern US. Updating current modeling frameworks with these observational constraints will also lead to more accurate treatment of aerosol formation for regions with substantial anthropogenic-biogenic interactions and consequently improve air quality and climate simulations.
by
June E. Pais;
Nan Dai;
Esta Tamanaha;
Romualdas Vaisvila;
Alexey I. Fomenkov;
Jurate Bitinaite;
Zhiyi Sun;
Shengxi Guan;
Ivan Correa;
Christopher J. Noren;
Xiaodong Cheng;
Richard J. Roberts;
Yu Zheng;
Lana Saleh
Modified DNA bases in mammalian genomes, such as 5-methylcytosine (<sup>5m</sup>C) and its oxidized forms, are implicated in important epigenetic regulation processes. In human or mouse, successive enzymatic conversion of <sup>5m</sup>C to its oxidized forms is carried out by the ten-eleven translocation (TET) proteins. Previously we reported the structure of a TET-like <sup>5m</sup>C oxygenase (NgTET1) from Naegleria gruberi, a single-celled protist evolutionarily distant from vertebrates. Here we show that NgTET1 is a 5-methylpyrimidine oxygenase, with activity on both <sup>5m</sup>C (major activity) and thymidine (T) (minor activity) in all DNA forms tested, and provide unprecedented evidence for the formation of 5-formyluridine (<sup>5f</sup>U) and 5-carboxyuridine (<sup>5ca</sup>U) in vitro. Mutagenesis studies reveal a delicate balance between choice of <sup>5m</sup>C or T as the preferred substrate. Furthermore, our results suggest substrate preference by NgTET1 to <sup>5m</sup>CpG and TpG dinucleotide sites in DNA. Intriguingly, NgTET1 displays higher T-oxidation activity in vitro than mammalian TET1, supporting a closer evolutionary relationship between NgTET1 and the base J-binding proteins from trypanosomes. Finally, we demonstrate that NgTET1 can be readily used as a tool in <sup>5m</sup>C sequencing technologies such as single molecule, realtime sequencing to map <sup>5m</sup>C in bacterial genomes at base resolution.
by
Diane G. Carnathan;
Katherine S. Wetzel;
Joana Yu;
S. Thera Lee;
Brent A. Johnson;
Mirko Paiardini;
Jian Yan;
Matthew P. Morrow;
Niranjan Y. Sardesai;
David B. Weiner;
Hildegund C. J. Ertl;
Guido Silvestri
An effective T-cell-based AIDS vaccine should induce strong HIV-specific CD8+T cells in mucosal tissues without increasing the availability of target cells for the virus. Here, we evaluated five immunization strategies that include Human adenovirus-5 (AdHu5), Chimpanzee adenovirus-6 (AdC6) or -7 (AdC7), Vaccinia virus (VV), and DNA given by electroporation (DNA/EP), all expressing Simian immunodeficiency virus group specific antigen/transactivator of transcription (SIVmac239Gag/Tat). Five groups of six rhesus macaques (RMs) each were vaccinated with DNA/EP-AdC6-AdC7, VV-AdC6-AdC7, DNA/-EPVV- AdC6, DNA/EP-VV-AdC7, or AdHu5-AdHu5-AdHu5 and were challenged repeatedly with low-dose intrarectal SIVmac239. Upon challenge, there were no significant differences among study groups in terms of virus acquisition or viral load after infection. When taken together, the immunization regimens did not protect against SIV acquisition compared with controls but did result in an ∼1.6-log decline in set-point viremia. Although all immunized RMs had detectable SIVspecific CD8+ T cells in blood and rectal mucosa, we found no correlation between the number or function of these SIV-specific CD8+ T cells and protection against SIV acquisition. Interestingly, RMs experiencing breakthrough infection showed significantly higher prechallenge levels of CD4+C-C chemokine receptor type 5 (CCR5)+HLA-DR+ T cells in the rectal biopsies (RB) than animals that remained uninfected. In addition, among the infected RMs, the percentage of CD4+CCR5+Ki- 67+ T cells in RBs prechallenge correlated with higher early viremia. Overall, these data suggest that the levels of activated CD4+CCR5+ target T cells in the rectal mucosa may predict the risk of SIV acquisition in RMs vaccinated with vectors that express SIVGag/Tat.
Langat virus (LGTV), one of the members of the tick-borne encephalitis virus (TBEV) complex, was firstly isolated from Ixodes granulatus ticks in Malaysia. However, the prevalence of LGTV in ticks in the region remains unknown. Surveillance for LGTV is therefore important and thus a tool for specific detection of LGTV is needed. In the present study, we developed a real-time quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) for rapid detection of LGTV. Our findings showed that the developed qRT-PCR could detect LGTV at a titre as low as 0.1 FFU/ml. The detection limit of the qRT-PCR assay at 95% probability was 0.28 FFU/ml as determined by probit analysis (p ≤ 0.05). Besides, the designed primers and probe did not amplify ORF of the E genes for some closely related and more pathogenic viruses including TBEV, Louping ill virus, Omsk hemorrhagic fever virus (OHFV), Alkhurma virus (ALKV), Kyasanur Forest Disease virus (KFDV) and Powassan virus (POWV) which showed the acceptable specificity of the developed assay. The sensitivity of the developed method also has been confirmed by determining the LGTV in infected tick cell line as well as LGTV- spiked tick tissues.
by
Rafidah Lani;
Pouya Hassandarvish;
Chun Wei Chiam;
Ehsan Moghaddam;
Justin Jang Hann Chu;
Kai Rausalu;
Andres Merits;
Stephen Higgs;
Dana Vanlandingham;
Sazaly Abu Bakar;
Keivan Zandi
The mosquito-borne chikungunya virus (CHIKV) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. Although there are several studies to evaluate the efficacy of drugs against CHIKV, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. Here, we investigated the antiviral activity of three types of flavonoids against CHIKV in vitro replication. Three compounds: silymarin, quercetin and kaempferol were evaluated for their in vitro antiviral activities against CHIKV using a CHIKV replicon cell line and clinical isolate of CHIKV of Central/East African genotype. A cytopathic effect inhibition assay was used to determine their activities on CHIKV viral replication and quantitative reverse transcription PCR was used to calculate virus yield. Antiviral activity of effective compound was further investigated by evaluation of CHIKV protein expression using western blotting for CHIKV nsP<inf>1</inf>, nsP<inf>3</inf>, and E<inf>2</inf>E<inf>1</inf> proteins. Briefly, silymarin exhibited significant antiviral activity against CHIKV, reducing both CHIKV replication efficiency and down-regulating production of viral proteins involved in replication. This study may have important consequence for broaden the chance of getting the effective antiviral for CHIKV infection.
by
Kaval Kaur;
Nai-Ying Zheng;
Kenneth Smith;
Min Huang;
Lie Li;
Noel T. Pauli;
Carole J. Henry Dunand;
Jane-Hwei Lee;
Michael Morrissey;
Yixuan Wu;
Michelle L. Joachims;
Melissa E. Munroe;
Denise Lau;
Xinyan Qu;
Florian Krammer;
Jens Wrammert;
Peter Palese;
Rafi Ahmed;
Judith A. James;
Patrick C. Wilson
Breakdown of B cell tolerance is a cardinal feature of systemic lupus erythematosus (SLE). Increased numbers of autoreactive mature naïve B cells have been described in SLE patients and autoantibodies have been shown to arise from autoreactive and non-autoreactive precursors. How these defects, in the regulation of B cell tolerance and selection, influence germinal center (GC) reactions that are directed towards foreign antigens has yet to be investigated. Here, we examined the characteristics of post-GC foreign antigen-specific B cells from SLE patients and healthy controls by analyzing monoclonal antibodies generated from plasmablasts induced specifically by influenza vaccination. We report that many of the SLE patients had anti-influenza antibodies with higher binding affinity and neutralization capacity than those from controls. Although overall frequencies of autoreactivity in the influenza-specific plasmablasts were similar for SLE patients and controls, the variable gene repertoire of influenza-specific plasmablasts from SLE patients was altered, with increased usage of JH6 and long heavy chain CDR3 segments. We found that high affinity anti-influenza antibodies generally characterize the plasmablast responses of SLE patients with low levels of autoreactivity; however, certain exceptions were noted. The high-avidity antibody responses in SLE patients may also be correlated with cytokines that are abnormally expressed in lupus. These findings provide insights into the effects of dysregulated immunity on the quality of antibody responses following influenza vaccination and further our understanding of the underlying abnormalities of lupus.
by
Urbain Weyemi;
Christophe E. Redon;
Towqir Aziz;
Rohini Choudhuri;
Daisuke Maeda;
Palak r. Parekh;
Michael Y. Bonner;
Jack Arbiser;
William M. Bonner
Ataxia telangiectasia (A-T), a rare autosomal recessive disorder characterized by progressive cerebellar degeneration and a greatly increased incidence of cancer among other symptoms, is caused by a defective or missing ataxia telangiectasia mutated (ATM) gene. The ATM protein has roles in DNA repair and in the regulation of reactive oxygen species (ROS). Here, we provide, to our knowledge, the first evidence that NADPH oxidase 4 (NOX4) is involved in manifesting A-T disease. We showed that NOX4 expression levels are higher in A-T cells, and that ATM inhibition leads to increased NOX4 expression in normal cells. A-T cells exhibit elevated levels of oxidative DNA damage, DNA double-strand breaks and replicative senescence, all of which are partially abrogated by down-regulation of NOX4 with siRNA. Sections of degenerating cerebelli from A-T patients revealed elevated NOX4 levels. ATM-null mice exhibit A-T disease but they die from cancer before the neurological symptoms are manifested. Injecting Atmnull mice with fulvene-5, a specific inhibitor of NOX4 and NADPH oxidase 2 (NOX2), decreased their elevated cancer incidence to that of the controls. We conclude that, in A-T disease in humans and mice, NOX4 may be critical mediator and targeting it will open up new avenues for therapeutic intervention in neurodegeneration.
by
Aaron D. Blackwell;
Marilyne Tamayo;
Bret Beheim;
Benjamin C. Trumble;
Jonathan Stieglitz;
Paul L. Hooper;
Melanie Martin;
Hillard Kaplan;
Michael Gurven
Infection with intestinal helminths results in immunological changes that influence co-infections, and might influence fecundity by inducing immunological states affecting conception and pregnancy.We investigated associations between intestinal helminths and fertility in women, using 9 years of longitudinal data from 986 Bolivian forager-horticulturalists, experiencing natural fertility and 70% helminth prevalence.We found that different species of helminth are associated with contrasting effects on fecundity. Infection with roundworm (Ascaris lumbricoides) is associated with earlier first births and shortened interbirth intervals, whereas infection with hookworm is associated with delayed first pregnancy and extended interbirth intervals. Thus, helminths may have important effects on human fertility that reflect physiological and immunological consequences of infection.
by
Andrew Folick;
Holly Doebbler Oakley;
Yong Yu;
Eric H. Armstrong;
Manju Kumari;
Lucas Sanor;
David D. Moore;
Eric Ortlund;
Rudolf Zechner;
Meng C. Wang
Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules.We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80.We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans.These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles inmetazoans.