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.
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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.
Autophagy, an ancient homeostasis mechanism for macromolecule degradation, performs an important role in host defense by facilitating pathogen elimination. To counteract this host defense strategy, bacterial pathogens have evolved a variety of mechanisms to avoid or otherwise dysregulate autophagy by phagocytic cells so as to enhance their survival during infection. Neisseria gonorrhoeae is a strictly human pathogen that causes the sexually transmitted infection, gonorrhea. Phosphoethanolamine (PEA) addition to the 4' position of the lipid A (PEA-lipid A) moiety of the lipooligosaccharide (LOS) produced by gonococci performs a critical role in this pathogen's ability to evade innate defenses by conferring decreased susceptibility to cationic antimicrobial (or host-defense) peptides, complementmediated killing by human serum and intraleukocytic killing by human neutrophils compared to strains lacking this PEA decoration. Heretofore, however, it was not known if gonococci can evade autophagy and if so, whether PEA-lipid A contributes to this ability. Accordingly, by using murine macrophages and human macrophage-like phagocytic cell lines we investigated if PEA decoration of gonococcal lipid A modulates autophagy formation. We report that infection with PEA-lipid A-producing gonococci significantly reduced autophagy flux in murine and human macrophages and enhanced gonococcal survival during their association with macrophages compared to a PEA-deficient lipid A mutant. Our results provide further evidence that PEA-lipid A produced by gonococci is a critical component in the ability of this human pathogen to evade host defenses. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
by
Hyman M. Scott;
Risha Irvin;
Leo Wilton;
Hong Van Tieu;
Chauncey Watson;
Manya Magnus;
Iris Chen;
Charlotte Gaydos;
Sophia Hussen;
Sharon Mannheimer;
Kenneth Mayer;
Nancy A. Hessol;
Susan Buchbinder
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Black men who have sex with men (MSM) have a high prevalence of bacterial sexually transmitted infections (STIs), and individual risk behavior does not fully explain the higher prevalence when compared with other MSM. Using the social-ecological framework, we evaluated individual, social and sexual network, and structural factors and their association with prevalent STIs among Black MSM. Methods: The HIV Prevention Trials Network 061 was a multi-site cohort study designed to determine the feasibility and acceptability of a multi-component intervention for Black MSM in six US cities. Baseline assessments included demographics, risk behavior, and social and sexual network questions collected information about the size, nature and connectedness of their sexual network. Logistic regression was used to estimate the odds of having any prevalent sexually transmitted infection (gonorrhea, chlamydia, or syphilis). Results: A total of 1,553 Black MSM were enrolled in this study. In multivariate analysis, older age (aOR = 0.57; 95% CI 0.49-0.66, p<0.001) was associated with a lower odds of having a prevalent STI. Compared with reporting one male sexual partner, having 2-3 partners (aOR = 1.74; 95% CI 1.08-2.81, p<0.024) or more than 4 partners (aOR = 2.29; 95% CI 1.43-3.66, p<0.001) was associated with prevalent STIs. Having both Black and non-Black sexual partners (aOR = 0.67; 95% CI 0.45-0.99, p = 0.042) was the only sexual network factor associated with prevalent STIs. Conclusions: Age and the number and racial composition of sexual partners were associated with prevalent STIs among Black MSM, while other sexual network factors were not. Further studies are needed to evaluate the effects of the individual, network, and structural factors on prevalent STIs among Black MSM to inform combination interventions to reduce STIs among these men.
by
Andrew W. Bergen;
Martha Michel;
Denise Nishita;
Ruth Krasnow;
Harold S. Javitz;
Karen Conneely;
Christina N. Lessov-Schlaggar;
Hyman Hops;
Andy Z. X. Zhu;
James W. Baurley;
Jennifer B. McClure;
Sharon M. Hall;
Timothy B. Baker;
David V. Conti;
Neal L. Benowitz;
Caryn Lerman;
Rachel F. Tyndale;
Gary E. Swan
The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 P<inf>ACT</inf>=4.1E-7, rs4803381 P<inf>ACT</inf>=4.5E-5, rs1137115, P<inf>ACT</inf>=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.
Deleted in colorectal cancer (DCC), a large transmembrane receptor of netrin-1, is critical for mediating netrin-1's cardioprotective function. In the present study we investigated novel mechanisms underlying netrin-1-induced, rapid, and feed-forward up-regulation of DCC, which is believed to sustain nitric oxide (NO) production to potentiate cardioprotection. Intriguingly, NO markedly reduced expression of the E3 ubiquitin ligase seven in absentia homolog (SIAH) that is specific for regulation of protesome-dependent DCC degradation, resulting in accumulation of DCC. The two SIAH isoforms compensate for each other when one is repressed; inhibition of both SIAH1 and SIAH2 using combined siRNAs significantly reduced infarct size while improving cardiac function after ischemia/reperfusion injury of the heart. This effect was absent in DCC-deficient mice. Moreover, in vivo RNAi inhibition of SIAH1/2 further augmented netrin-1's cardioprotective function. In summary, these data identify a novel therapeutic target of SIAH in facilitating NO/netrin-1-dependent cardioprotection, using the DCC receptor. Combination of netrin-1 and SIAH RNAi may prove to be a substantially effective therapy for myocardial infarction.
by
Daniel Claiborne;
Jessica Prince;
Eileen Scully;
Gladys Macharia;
Luca Micci;
Benton Lawson;
Jakub Kopycinski;
Martin J. Deymier;
Thomas Vanderford;
Krystelle Nganou-Makamdop;
Zachary Ende;
Kelsie Brooks;
Jianming Tang;
Tianwei Yu;
Shabir Lakhi ;
William Kilembe;
Guido Silvestri;
Daniel Douek;
Paul A. Goepfert;
Matthew A. Price;
Susan A. Allen;
Mirko Paiardini;
Marcus Altfeld;
Jill Gilmour;
Eric Hunter
HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.
This study examined the prevalence and characteristics of autism spectrum disorder (ASD), cerebral palsy (CP), hearing loss (HL), intellectual disability (ID), and vision impairment (VI) over a 15-20 year time period, with specific focus on concurrent changes in ASD and ID prevalence. We used data from a population-based developmental disabilities surveillance program for 8-year-olds in metropolitan Atlanta. From 1991-2010, prevalence estimates of ID and HL were stable with slight increases in VI prevalence. CP prevalence was constant from 1993-2010. The average annual increase in ASD prevalence was 9.3% per year from 1996-2010, with a 269% increase from 4.2 per 1,000 in 1996 to 15.5 per 1,000 in 2010. From 2000-2010, the prevalence of ID without ASD was stable; during the same time, the prevalence of ASD with and without co-occurring ID increased by an average of 6.6% and 9.6% per year, respectively. ASD prevalence increases were found among both males and females, and among nearly all racial/ethnic subgroups and levels of intellectual ability. Average annual prevalence estimates from 1991-2010 underscore the significant community resources needed to provide early intervention and ongoing supports for children with ID (13.0 per 1,000), CP, (3.5 per 1,000), HL (1.4 per 1,000) and VI (1.3 in 1,000), with a growing urgency for children with ASD.
CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90.
When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R2 ∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell-based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cell-based vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.
Couples HIV Testing and Counseling (CHTC) has been used as an HIV prevention strategy in Africa for over 20 years where the HIV epidemic is largely concentrated among sexually active heterosexuals. In recent years, CHTC has been adapted for men who have sex with men (MSM) in the US. A central element of the CHTC intervention as adapted for male couples in the US is the discussion of sexual agreements by the dyad during the CHTC session. Given the success of CHTC for heterosexual couples in Africa, it seems appropriate that CHTC could also be provided to heterosexual couples in the US. However, little is known about heterosexual’s willingness to utilize CHTC services including discussion of sexual agreements. This small, preliminary qualitative study sheds new light on the potential for CHTC adoption among heterosexuals in the US. Four focus groups were conducted with heterosexual men and women attending a publicly-funded STI clinic, to explore the potential feasibility and acceptability of CHTC with heterosexuals. The results are similar to those seen for MSM: high levels of willingness to use CHTC, perceptions of the advantages of using CHTC, and willingness to discuss sexual agreements; all necessary conditions for the successful roll-out of CHTC. Further work is now needed with larger samples of high-risk heterosexuals to more completely understand the typologies of sexual agreements and the common language used for sexual agreements in heterosexual relationships. These early data show great promise that CHTC can achieve the same levels of willingness, fit, and acceptability among heterosexual couples as currently experienced by male couples in the US.