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

The association between parity, infant gender, higher level of paternal education and preterm birth in Pakistan: a cohort study

<p>Abstract</p> <p>Background</p> <p>High rates of antenatal depression and preterm birth have been reported in Pakistan. Self reported maternal stress and depression have been associated with preterm birth; however findings are inconsistent. Cortisol is a biological marker of stress and depression, and its measurement may assist in understanding the influence of self reported maternal stress and depression on preterm birth.</p> <p>Methods</p> <p>In a prospective cohort study pregnant women between 28 to 30 weeks of gestation from the Aga Khan Hospital for Women and Children completed the A-Z Stress Scale and the Centre for Epidemiology Studies Depression Scale to assess stress and depression respectively, and had a blood cortisol level drawn. Women were followed up after delivery to determine birth outcomes. Correlation coefficients and Wilcoxon rank sum test was used to assess relationship between preterm birth, stress, depression and cortisol. Logistic regression analysis was used to determine the key factors predictive of preterm birth.</p> <p>Results</p> <p>132 pregnant women participated of whom 125 pregnant women had both questionnaire and cortisol level data and an additional seven had questionnaire data only. Almost 20% of pregnant women (19·7%, 95% CI 13·3-27·5) experienced a high level of stress and nearly twice as many (40·9%, 95% CI 32·4-49·8%) experienced depressive symptoms. The median of cortisol level was 27·40 ug/dl (IQR 22·5-34·2). The preterm birth rate was 11·4% (95% CI 6·5-18). There was no relationship between cortisol values and stress scale or depression. There was a significant positive relationship between maternal depression and stress. Preterm birth was associated with higher parity, past delivery of a male infant, and higher levels of paternal education. Insufficient numbers of preterm births were available to warrant the development of a multivariable logistic regression model.</p> <p>Conclusions</p> <p>Preterm birth was associated with higher parity, past delivery of a male infant, and higher levels of paternal education. There was no relationship between stress, and depression, cortisol and preterm birth. There were high rates of stress and depression among this sample suggesting that there are missed opportunities to address mental health needs in the prenatal period. Improved methods of measurement are required to better understand the psychobiological basis of preterm birth.</p

A novel approach : the propensity to propagate (PTP) method for controlling for host factors in studying the transmission of Mycobacterium tuberculosis

RATIONALE: Understanding the genetic variations among Mycobacterium tuberculosis (MTB) strains with differential ability to transmit would be a major step forward in preventing transmission. OBJECTIVES: To describe a method to extend conventional proxy measures of transmissibility by adjusting for patient-related factors, thus strengthening the causal association found with bacterial factors. METHODS: Clinical, demographic and molecular fingerprinting data were obtained during routine surveillance of verified MTB cases reported in the Netherlands between 1993 and 2011, and the phylogenetic lineages of the isolates were inferred. Odds ratios for host risk factors for clustering were used to obtain a measure of each patient's and cluster's propensity to propagate (CPP). Mean and median cluster sizes across different categories of CPP were compared amongst four different phylogenetic lineages. RESULTS: Both mean and median cluster size grew with increasing CPP category. On average, CPP values from Euro-American lineage strains were higher than Beijing and EAI strains. There were no significant differences between the mean and median cluster sizes among the four phylogenetic lineages within each CPP category. CONCLUSIONS: Our finding that the distribution of CPP scores was unequal across four different phylogenetic lineages supports the notion that host-related factors should be controlled for to attain comparability in measuring the different phylogenetic lineages' ability to propagate. Although Euro-American strains were more likely to be in clusters in an unadjusted analysis, no significant differences among the four lineages persisted after we controlled for host factors.Portuguese Foundation for Science and Technology (FCT) (SFRH/BD/33902/2009 to HN-G). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Behavior Problems in Relation to Sustained Selective Attention Skills of Moderately Preterm Children

Attention skills may form an important developmental mechanism. A mediation model was examined in which behavioral problems of moderately preterm and term children at school age are explained by attention performance. Parents and teachers completed behavioral assessments of 348 moderately preterm children and 182 term children at 8 years of age. Children were administered a test of sustained selective attention. Preterm birth was associated with more behavioral and attention difficulties. Gestational age, prenatal maternal smoking, and gender were associated with mothers’, fathers’, and teachers’ reports of children’s problem behavior. Sustained selective attention partially mediated the relationship between birth status and problem behavior. Development of attention skills should be an important focus for future research in moderately preterm children

HIV-1 prevalence and factors associated with infection in the conflict-affected region of North Uganda

BACKGROUND: Since 1986, northern Uganda has been severely affected by civil strife with most of its population currently living internally displaced in protected camps. This study aims at estimating the HIV-1 prevalence among this population and the factors associated with infection. METHODS: In June-December 2005, a total of 3051 antenatal clinics attendees in Gulu, Kitgum and Pader districts were anonymously tested for HIV-1 infection as part of routine sentinel surveillance. Factors associated with the infection were evaluated using logistic regression models. RESULTS: The age-standardised HIV-1 prevalence was 10.3%, 9.1% and 4.3% in the Gulu, Kitgum and Pader district, respectively. The overall prevalence in the area comprised of these districts was 8.2% when data was weighted according to the districts' population size. Data from all sites combined show that, besides older women [20–24 years: adjusted odds ratio (AOR) = 1.96, 95% confidence interval (CI): 1.29–2.97; 25–29 years: AOR = 2.01, 95% CI: 1.30–3.11; ≥ 30 years: AOR = 1.91, 95% CI: 1.23–2.97], unmarried women (AOR = 1.47, 95% CI: 1.06–2.04), and those with a partner with a non-traditional occupation (AOR = 1.62, 95% CI: 1.18–2.21), women living outside of protected camps for internally displaced persons have a higher risk of being HIV-1 infected than internally displaced women (AOR = 1.55, 95% CI: 1.15–2.08). CONCLUSION: Although published data from Gulu district show a declining HIV-1 prevalence trend that is consistent with that observed at the national level since 1993, the prevalence in North Uganda is still high. Internally displaced women have a lower risk of being infected probably because of their reduced mobility and accessibility, and increased access to health prevention services

No more 'business as usual' with audit and feedback interventions: towards an agenda for a reinvigorated intervention

Background: Audit and feedback interventions in healthcare have been found to be effective, but there has been little progress with respect to understanding their mechanisms of action or identifying their key ‘active ingredients.’ Discussion: Given the increasing use of audit and feedback to improve quality of care, it is imperative to focus further research on understanding how and when it works best. In this paper, we argue that continuing the ‘business as usual’ approach to evaluating two-arm trials of audit and feedback interventions against usual care for common problems and settings is unlikely to contribute new generalizable findings. Future audit and feedback trials should incorporate evidence- and theory-based best practices, and address known gaps in the literature. Summary: We offer an agenda for high-priority research topics for implementation researchers that focuses on reviewing best practices for designing audit and feedback interventions to optimize effectiveness

CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model.

Abstract Background Macrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored. Methods Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density. Results Overexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density. Conclusions Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density

Proteomic Changes Resulting from Gene Copy Number Variations in Cancer Cells

Along the transformation process, cells accumulate DNA aberrations, including mutations, translocations, amplifications, and deletions. Despite numerous studies, the overall effects of amplifications and deletions on the end point of gene expression—the level of proteins—is generally unknown. Here we use large-scale and high-resolution proteomics combined with gene copy number analysis to investigate in a global manner to what extent these genomic changes have a proteomic output and therefore the ability to affect cellular transformation. We accurately measure expression levels of 6,735 proteins and directly compare them to the gene copy number. We find that the average effect of these alterations on the protein expression is only a few percent. Nevertheless, by using a novel algorithm, we find the combined impact that many of these regional chromosomal aberrations have at the protein level. We show that proteins encoded by amplified oncogenes are often overexpressed, while adjacent amplified genes, which presumably do not promote growth and survival, are attenuated. Furthermore, regulation of biological processes and molecular complexes is independent of general copy number changes. By connecting the primary genome alteration to their proteomic consequences, this approach helps to interpret the data from large-scale cancer genomics efforts