Determinants of serum concentrations of organochlorine compounds in Swedish pregnant women: a cross-sectional study

BACKGROUND: We performed a cross-sectional study of associations between personal characteristics and lipid-adjusted serum concentrations of certain PCB congeners and chlorinated pesticides/metabolites among 323 pregnant primiparous women from Uppsala County (age 18–41 years) sampled 1996–1999. METHODS: Extensive personal interviews and questionnaires about personal characteristics were performed both during and after pregnancy. Concentrations of organochlorine compounds in serum lipids in late pregnancy were analysed by gas chromatography. Associations between personal characteristics and serum levels of organochlorine compounds were analysed by multiple linear regression. RESULTS: Participation rate was 82% (325 of 395 women). Serum concentrations of PCB congeners IUPAC no. 28, 52, 101, 105 and 167, and o, p'-DDT and -DDE, p, p'-DDT and -DDD, oxychlordane, and γ- and α-HCH were in many cases below the limit of quantification (LOQ). No statistical analysis of associations with personal characteristics could be performed for these substances. Concentrations of PCB congeners IUPAC no. 118, 138, 153, 156 and 180, HCB, β-HCH, trans-nonachlor and p, p'-DDE increased with increased age and were highest in women sampled early during the 4 year study period. This shows that older women and women sampled early in the study had experienced the highest life-time exposure levels, probably mainly during childhood and adolescence. The importance of early exposures was supported by lower PCB concentrations and higher β-HCH and p, p'-DDE concentrations among women born in non-Nordic countries. Moreover, serum concentrations of certain PCBs and pesticide/metabolites were positively associated with consumption of fatty fish during adolescence, and concentrations of CB 156, CB 180 and p, p'-DDE increased significantly with number of months women had been breast-fed during infancy. Short-term changes in bodily constitution may, however, also influence serum concentrations, as suggested by negative associations between concentrations of organochlorine compounds and BMI before pregnancy and weight change during pregnancy. CONCLUSION: Although some of the associations could be caused by unknown personal characteristics confounding the results, our findings suggest that exposures to organochlorine compounds during childhood and adolescence influence the body burdens of the compounds during pregnancy

Principles of meiotic chromosome assembly revealed in S. cerevisiae

During meiotic prophase, chromosomes organise into a series of chromatin loops emanating from a proteinaceous axis, but the mechanisms of assembly remain unclear. Here we use Saccharomyces cerevisiae to explore how this elaborate three-dimensional chromosome organisation is linked to genomic sequence. As cells enter meiosis, we observe that strong cohesin-dependent grid-like Hi-C interaction patterns emerge, reminiscent of mammalian interphase organisation, but with distinct regulation. Meiotic patterns agree with simulations of loop extrusion with growth limited by barriers, in which a heterogeneous population of expanding loops develop along the chromosome. Importantly, CTCF, the factor that imposes similar features in mammalian interphase, is absent in S. cerevisiae, suggesting alternative mechanisms of barrier formation. While grid-like interactions emerge independently of meiotic chromosome synapsis, synapsis itself generates additional compaction that matures differentially according to telomere proximity and chromosome size. Collectively, our results elucidate fundamental principles of chromosome assembly and demonstrate the essential role of cohesin within this evolutionarily conserved process

Gene expression model (in)validation by Fourier analysis

The determination of the right model structure describing a gene regulation network and the identification of its parameters are major goals in systems biology. The task is often hampered by the lack of relevant experimental data with sufficiently low noise level, but the subset of genes whose concentration levels exhibit an oscillatory behavior in time can readily be analyzed on the basis of their Fourier spectrum, known to turn complex signals into few relatively noise-free parameters. Such genes therefore offer opportunities of understanding gene regulation quantitatively.Journal ArticleResearch Support, Non-U.S. Gov'tValidation StudiesSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Structural basis of nucleosome assembly by the Abo1 AAA+ ATPase histone chaperone

The fundamental unit of chromatin, the nucleosome, is an intricate structure that requires histone chaperones for assembly. ATAD2 AAA+???ATPases are a family of histone chaperones that regulate nucleosome density and chromatin dynamics. Here, we demonstrate that the fission yeast ATAD2 homolog, Abo1, deposits histone H3???H4 onto DNA in an ATP-hydrolysis-dependent manner by in vitro reconstitution and single-tethered DNA curtain assays. We present cryo-EM structures of an ATAD2 family ATPase to atomic resolution in three different nucleotide states, revealing unique structural features required for histone loading on DNA, and directly visualize the transitions of Abo1 from an asymmetric spiral (ATP-state) to a symmetric ring (ADP- and apo-states) using high-speed atomic force microscopy (HS-AFM). Furthermore, we find that the acidic pore of ATP-Abo1 binds a peptide substrate which is suggestive of a histone tail. Based on these results, we propose a model whereby Abo1 facilitates H3???H4 loading by utilizing ATP

Global Profiling of DNA Replication Timing and Efficiency Reveals that Efficient Replication/Firing Occurs Late during S-Phase in S. pombe

10.1371/journal.pone.0000722PLoS ONE2

Episodic Therapy for Genital Herpes in Sub-Saharan Africa: A Pooled Analysis from Three Randomized Controlled Trials

BACKGROUND: A randomized controlled trial in South Africa found a beneficial effect of acyclovir on genital ulcer healing, but no effect was seen in trials in Ghana, Central African Republic and Malawi. The aim of this paper is to assess whether the variation in impact of acyclovir on ulcer healing in these trials can be explained by differences in the characteristics of the study populations. METHODOLOGY/PRINCIPAL FINDINGS: Pooled data were analysed to estimate the impact of acyclovir on the proportion of ulcers healed seven days after randomisation by HIV/CD4 status, ulcer aetiology, size and duration before presentation; and impact on lesional HIV-1. Risk ratios (RR) were estimated using Poisson regression with robust standard errors. Of 1478 patients with genital ulcer, most (63%) had herpetic ulcers (16% first episode HSV-2 ulcers), and a further 3% chancroid, 2% syphilis, 0.7% lymphogranuloma venereum and 31% undetermined aetiology. Over half (58%) of patients were HIV-1 seropositive. The median duration of symptoms before presentation was 6 days. Patients on acyclovir were more likely to have a healed ulcer on day 7 (63% vs 57%, RR = 1.08, 95% CI 0.98-1.18), shorter time to healing (p = 0.04) and less lesional HIV-1 RNA (p = 0.03). Small ulcers (<50 mm(2)), HSV-2 ulcers, first episode HSV-2 ulcers, and ulcers in HIV-1 seropositive individuals responded best but the better effectiveness in South Africa was not explained by differences in these factors. CONCLUSIONS/SIGNIFICANCE: There may be slight benefit in adding acyclovir to syndromic management in settings where most ulcers are genital herpes. The stronger effect among HIV-1 infected individuals suggests that acyclovir may be beneficial for GUD/HIV-1 co-infected patients. The high prevalence in this population highlights that genital ulceration in patients with unknown HIV status provides a potential entry point for provider-initiated HIV testing

Multimorbidity prevalence and patterns across socioeconomic determinants: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Studies on the prevalence of multimorbidity, defined as having two or more chronic conditions, have predominantly focused on the elderly. We estimated the prevalence and specific patterns of multimorbidity across different adult age groups. Furthermore, we examined the associations of multimorbidity with socio-demographic factors.</p> <p>Methods</p> <p>Using data from the Health Quality Council of Alberta (HQCA) 2010 Patient Experience Survey, the prevalence of self reported multimorbidity was assessed by telephone interview among a sample of 5010 adults (18 years and over) from the general population. Logistic regression analyses were performed to determine the association between a range of socio-demographic factors and multimorbidity.</p> <p>Results</p> <p>The overall age- and sex-standardized prevalence of multimorbidity was 19.0% in the surveyed general population. Of those with multimorbidity, 70.2% were aged less than 65 years. The most common pairing of chronic conditions was chronic pain and arthritis. Age, sex, income and family structure were independently associated with multimorbidity.</p> <p>Conclusions</p> <p>Multimorbidity is a common occurrence in the general adult population, and is not limited to the elderly. Future prevention programs and practice guidelines should take into account the common patterns of multimorbidity.</p

Displacement and re-accumulation of centromeric cohesin during transient pre-anaphase centromere splitting

The ring-shaped cohesin complex links sister chromatids until their timely segregation during mitosis. Cohesin is enriched at centromeres where it provides the cohesive counterforce to bipolar tension produced by the mitotic spindle. As a consequence of spindle tension, centromeric sequences transiently split in pre-anaphase cells, in some organisms up to several micrometers. This ‘centromere breathing’ presents a paradox, how sister sequences separate where cohesin is most enriched. We now show that in the budding yeast Saccharomyces cerevisiae, cohesin binding diminishes over centromeric sequences that split during breathing. We see no evidence for cohesin translocation to surrounding sequences, suggesting that cohesin is removed from centromeres during breathing. Two pools of cohesin can be distinguished. Cohesin loaded before DNA replication, which has established sister chromatid cohesion, disappears during breathing. In contrast, cohesin loaded after DNA replication is partly retained. As sister centromeres re-associate after transient separation, cohesin is reloaded in a manner independent of the canonical cohesin loader Scc2/Scc4. Efficient centromere re-association requires the cohesion establishment factor Eco1, suggesting that re-establishment of sister chromatid cohesion contributes to the dynamic behaviour of centromeres in mitosis. These findings provide new insights into cohesin behaviour at centromeres

The Elg1 Clamp Loader Plays a Role in Sister Chromatid Cohesion

Mutations in the ELG1 gene of yeast lead to genomic instability, manifested in high levels of genetic recombination, chromosome loss, and gross chromosomal rearrangements. Elg1 shows similarity to the large subunit of the Replication Factor C clamp loader, and forms a RFC-like (RLC) complex in conjunction with the 4 small RFC subunits. Two additional RLCs exist in yeast: in one of them the large subunit is Ctf18, and in the other, Rad24. Ctf18 has been characterized as the RLC that functions in sister chromatid cohesion. Here we present evidence that the Elg1 RLC (but not Rad24) also plays an important role in this process. A genetic screen identified the cohesin subunit Mcd1/Scc1 and its loader Scc2 as suppressors of the synthetic lethality between elg1 and ctf4. We describe genetic interactions between ELG1 and genes encoding cohesin subunits and their accessory proteins. We also show that defects in Elg1 lead to higher precocious sister chromatid separation, and that Ctf18 and Elg1 affect cohesion via a joint pathway. Finally, we localize both Ctf18 and Elg1 to chromatin and show that Elg1 plays a role in the recruitment of Ctf18. Our results suggest that Elg1, Ctf4, and Ctf18 may coordinate the relative movement of the replication fork with respect to the cohesin ring

Getting research into policy - Herpes simplex virus type-2 (HSV-2) treatment and HIV infection: international guidelines formulation and the case of Ghana

BACKGROUND: Observational epidemiological and biological data indicate clear synergies between Herpes simplex virus type 2 (HSV-2) and HIV, whereby HSV-2 enhances the potential for HIV acquisition or transmission. In 2001, the World Health Organization (WHO) launched a call for research into the possibilities of disrupting this cofactor effect through the use of antiherpetic therapy. A WHO Expert Meeting was convened in 2008 to review the research results. The results of the trials were mostly inconclusive or showed no impact. However, the WHO syndromic management treatment guidelines were modified to include acyclovir as first line therapy to treat genital ulcer disease on the basis of the high prevalence of HSV-2 in most settings, impact and cost-benefit of treatment on ulcer healing and quality of life among patients. METHODS: This paper examines the process through which the evidence related to HIV-HSV-2 interactions influenced policy at the international level and then the mechanism of international to national policy transfer, with Ghana as a case study. To better understand the context within which national policy change occurs, special attention was paid to the relationships between researchers and policy-makers as integral to the process of getting evidence into policy. Data from this study were then collected through interviews conducted with researchers, program managers and policy-makers working in sexual health/STI at the 2008 WHO Expert Meeting in Montreux, Switzerland, and in Accra, Ghana. RESULTS: The major findings of this study indicate that investigations into HSV-2 as a cofactor of HIV generated the political will necessary to reform HSV-2 treatment policy. Playing a pivotal role at both the international level and within the Ghanaian policy context were 'policy networks' formed either formally (WHO) or informally (Ghana) around an issue area. These networks of professionals serve as the primary conduit of information between researchers and policy-makers. Donor influence was cited as the single strongest impetus and impediment to policy change nationally. CONCLUSIONS: Policy networks may serve as the primary driving force of change in both international context and in the case of Ghana. Communication among researchers and policy-makers is critical for uptake of evidence and opportunities may exist to formalize policy networks and engage donors in a productive and ethical way