Control of replication initiation by the Sum1/Rfm1/Hst1 histone deacetylase

<p>Abstract</p> <p>Background</p> <p>Replication initiation at origins of replication in the yeast genome takes place on chromatin as a template, raising the question how histone modifications, for instance histone acetylation, influence origin firing. Initiation requires binding of the replication initiator, the Origin Recognition Complex (ORC), to a consensus sequence within origins. In addition, other proteins bind to recognition sites in the vicinity of ORC and support initiation. In previous work, we identified Sum1 as an origin-binding protein that contributes to efficient replication initiation. Sum1 is part of the Sum1/Rfm1/Hst1 complex that represses meiotic genes during vegetative growth via histone deacetylation by the histone deacetylase (HDAC) Hst1.</p> <p>Results</p> <p>In this study, we investigated how Sum1 affected replication initiation. We found that it functioned in initiation as a component of the Sum1/Rfm1/Hst1 complex, implying a role for histone deacetylation in origin activity. We identified several origins in the yeast genome whose activity depended on both Sum1 and Hst1. Importantly, <it>sum1</it>Δ or <it>hst1</it>Δ caused a significant increase in histone H4 lysine 5 (H4 K5) acetylation levels, but not other H4 acetylation sites, at those origins. Furthermore, mutation of lysines to glutamines in the H4 tail, which imitates the constantly acetylated state, resulted in a reduction of origin activity comparable to that in the absence of Hst1, showing that deacetylation of H4 was important for full initiation capacity of these origins.</p> <p>Conclusion</p> <p>Taken together, our results demonstrate a role for histone deacetylation in origin activity and reveal a novel aspect of origin regulation by chromatin. These results suggest recruitment of the Sum1/Rfm1/Hst1 complex to a number of yeast origins, where Hst1 deacetylated H4 K5.</p

Challenges in Estimating the Causal Effect of an Intervention with Pre-Post Data (Part 1): Definition & Identification of the Causal Parameter

There is mixed evidence of the effectiveness of interventions operating on a large scale. Although the lack of consistent results is generally attributed to problems of implementation or governance of the program, the failure to find a statistically significant effect (or the success of finding one) may be due to choices made in the evaluation. To demonstrate the potential limitations and pitfalls of the usual analytic methods used for estimating causal effects, we apply the first half of a roadmap for causal inference to a pre-post evaluation of a community-level, national nutrition program. Selection into the program was non-random and strongly associated with the pre-treatment (lagged) outcome. Using structural causal models (SCM), directed acyclic graphs (DAGs) and simulated data, we demonstrate that a post treatment estimand controls for confounding by the lagged outcome but not from possible unmeasured confounders. Two separate difference-in-differences estimands have the potential to adjust for a certain type of unmeasured confounding, but introduce bias if the additional assumptions they require are not met. Our results reveal an important issue of identifiability when estimating the causal effect of a program with pre-post observational data. A careful appraisal of the assumptions underlying the causal model is imperative before committing to a statistical model and progressing to estimation

Gender equality and global health: intersecting political challenges.

BACKGROUND: Women's and men's health outcomes are different. Some differences are biological, related to male and female sex, while others are related to their gender. Sex- and gender-related issues require different solutions, but policy makers lack straightforward heuristic strategies to identify gender-related health inequities. METHODS: Using 169 causes of disability-adjusted life years (DALYs) from the 2017 Global Burden of Disease, we calculated the female-to-male (f:m) and male-to-female (m:f) ratios of global DALYs, rank-ordered the ratios by size and calculated the proportion of all-cause DALYs that each cause explained, separately for males and females 15-49 years old. Gender-related vs sex-related causes were categorised using literature on the drivers for the 15 causes with highest f:m and m:f ratios. RESULTS: Causes of DALYs with high m:f ratios appear to be gendered and include: road injuries, interpersonal violence, and drowning - totaling 12.4% of men's (15-49 years) all-cause DALYs. However, causes of DALYs with high f:m ratios are more likely a mix of sex-related and gender-related factors - including headache disorders, depressive disorders, and dietary iron deficiency - totaling 13.4% of women's (15-49 years) all-cause DALYs. Ratios vary by age, geography and Socio-demographic Index. CONCLUSIONS: Gender-related vs sex-related causes were categorised using available literature on the drivers for selected causes, illustrating that sex-disaggregated data represents a mix of social and biological influences. This analysis offers a model that policy makers can use to uncover potential gender inequalities in health, including intersections with other social factors. From it, new challenges emerge for global health policy makers and practitioners willing to address them. Global health actors will need to achieve a balance between the two agendas of global health and gender equality

What Happens During Language and Literacy Coaching? Coaches’ Reports of Their Interactions With Educators

Research Findings: This study investigated coaches’ interactions with educators in the context of a large-scale, state-implemented literacy professional development (PD). We examined log data and open-comment reports to understand what coaches found salient about their interactions with educators as well as how those reports aligned with the initial design of the PD. Coaches reported spending a large proportion of their interactions with educators completing administrative tasks. Our findings also indicate that coaches disproportionally targeted instructional content from the PD while also adding unrelated instructional content to their coaching. Although coaches reported focusing on relationship building, they reported using less efficacious coaching strategies (e.g., observation and discussion) more frequently than coaching strategies demonstrated to be more efficacious (e.g., modeling and co-teaching). Practice or Policy: Our findings suggest an explanation for the mixed evidence around coaching, as coaches in the study seemed to move beyond the specifications of the PD in their coaching interactions. This work has implications for the design of PD for both improving coach training and allowing some flexibility to meet educators’ learning needs that may be secondary to the content of the PD. Findings also support the need for more nuanced mechanisms for investing in coaching and coaching outcomes

What Happens During Language and Literacy Coaching? Coaches’ Reports of Their Interactions With Educators

Research Findings: This study investigated coaches’ interactions with educators in the context of a large-scale, state-implemented literacy professional development (PD). We examined log data and open-comment reports to understand what coaches found salient about their interactions with educators as well as how those reports aligned with the initial design of the PD. Coaches reported spending a large proportion of their interactions with educators completing administrative tasks. Our findings also indicate that coaches disproportionally targeted instructional content from the PD while also adding unrelated instructional content to their coaching. Although coaches reported focusing on relationship building, they reported using less efficacious coaching strategies (e.g., observation and discussion) more frequently than coaching strategies demonstrated to be more efficacious (e.g., modeling and co-teaching). Practice or Policy: Our findings suggest an explanation for the mixed evidence around coaching, as coaches in the study seemed to move beyond the specifications of the PD in their coaching interactions. This work has implications for the design of PD for both improving coach training and allowing some flexibility to meet educators’ learning needs that may be secondary to the content of the PD. Findings also support the need for more nuanced mechanisms for investing in coaching and coaching outcomes

What Happens During Language and Literacy Coaching? Coaches’ Reports of Their Interactions With Educators

Research Findings: This study investigated coaches’ interactions with educators in the context of a large-scale, state-implemented literacy professional development (PD). We examined log data and open-comment reports to understand what coaches found salient about their interactions with educators as well as how those reports aligned with the initial design of the PD. Coaches reported spending a large proportion of their interactions with educators completing administrative tasks. Our findings also indicate that coaches disproportionally targeted instructional content from the PD while also adding unrelated instructional content to their coaching. Although coaches reported focusing on relationship building, they reported using less efficacious coaching strategies (e.g., observation and discussion) more frequently than coaching strategies demonstrated to be more efficacious (e.g., modeling and co-teaching). Practice or Policy: Our findings suggest an explanation for the mixed evidence around coaching, as coaches in the study seemed to move beyond the specifications of the PD in their coaching interactions. This work has implications for the design of PD for both improving coach training and allowing some flexibility to meet educators’ learning needs that may be secondary to the content of the PD. Findings also support the need for more nuanced mechanisms for investing in coaching and coaching outcomes

A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis

More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reporte

The interrelationship between water access, exclusive breastfeeding and diarrhea in children: a cross-sectional assessment across 19 African countries

Background Access to an improved water supply and practicing exclusive breastfeeding are essential for improving maternal and child health outcomes. However, few studies have been equipped to assess the interdependencies between access to improved water, practicing exclusive breastfeeding, and child health. The primary aim of our study was to assess whether access to an improved water supply and water-fetching were associated with mothers’ practice of exclusive breastfeeding. Methods We analyzed data on 247090 mothers with children 5 months old or less using Multiple Indicator Cluster Surveys from 19 African countries. Multivariable logistic regression was used to estimate the relationship between our exposures and exclusive breastfeeding practice, while meta-analytic methods were used to pool adjusted estimates across 19 countries. Results The prevalence of exclusive breastfeeding ranged from 22% in Nigeria to 70% in Malawi. Pooled results showed water-fetching was not associated with exclusive breastfeeding (adjusted prevalence odds ratios (aPOR)=1.04, 95% confidence interval (CI)=0.89, 1.21). Access to an improved water source was also not associated with exclusive breastfeeding (aPOR=1.06, 95% CI=0.94, 1.21). Across all countries many women were spending a significant amount of time water-fetching each day (mean time varied from 20 minutes in Ghana to 115 minutes in Mauritania). Exclusively breastfed children had 33% lower odds of diarrhea than those who were not exclusively breastfed (aPOR=0.67, 95% CI=0.56, 0.78). Conclusion Our study is the first to assess the relationship between access to improved water supply, water-fetching and exclusive breastfeeding. We found that access to water supply and time spent by mothers fetching water were not associated with exclusive breastfeeding practice, even though mothers spent significant time fetching wate

Perpetration of intimate partner violence and mental health outcomes: sex- and gender-disaggregated associations among adolescents and young adults in Nigeria.

BACKGROUND: The association between intimate partner violence (IPV) victimisation and poor mental health outcomes is well established. Less is known about the correlation between IPV perpetration and mental health, particularly among adolescents and young adults. Using data from the nationally representative Violence Against Children Survey, this analysis examines the association between IPV perpetration and mental health for male and female adolescents and young adults in Nigeria. METHODS: Multivariate logistic regression models were used to examine associations between ever-perpetration of IPV and four self-reported mental health variables: severe sadness, feelings of worthlessness, suicide ideation, and alcohol use. Models were sex-disaggregated, controlled for age, marital status, and schooling, and tested with and without past exposure to violence. Standard errors were adjusted for sampling stratification and clustering. Observations were weighted to be representative of 13-24 year-olds in Nigeria. RESULTS: Males were nearly twice as likely as females to perpetrate IPV (9% v. 5%, respectively; P < 0.001), while odds of perpetration for both sexes were higher for those ever experiencing IPV (adjusted odds ratio (aOR) = 4.60 for males; aOR = 2.71 for females). Female perpetrators had 2.73 higher odds of reporting severe sadness (95% confidence interval CI = 1.44, 5.17; P = 0.002) and 2.72 times greater odds of reporting suicide ideation (1.28, 5.79; P = 0.010) than non-perpetrating females, even when controlling for past-year violence victimisation. In contrast, male perpetrators had 2.65 times greater odds of feeling worthless (1.09, 6.43; P = 0.031), and 2.36 times greater odds of reporting alcohol use in the last 30 days (1.50, 3.73; P < 0.001), as compared to non-perpetrating males. CONCLUSIONS: Among adolescents and young adults in Nigeria, IPV perpetration and negative mental health outcomes are associated but differ for males and females. Mindful of the cross-sectional nature of the data, it is possible that socially determined gender norms may shape the ways in which distress from IPV perpetration is understood and expressed. Additional research is needed to clarify these associations and inform violence prevention efforts