Mitotic H3K9ac is controlled by phase-specific activity of HDAC2, HDAC3, and SIRT1.

Histone acetylation levels are reduced during mitosis. To study the mitotic regulation of H3K9ac, we used an array of inhibitors targeting specific histone deacetylases. We evaluated the involvement of the targeted enzymes in regulating H3K9ac during all mitotic stages by immunofluorescence and immunoblots. We identified HDAC2, HDAC3, and SIRT1 as modulators of H3K9ac mitotic levels. HDAC2 inhibition increased H3K9ac levels in prophase, whereas HDAC3 or SIRT1 inhibition increased H3K9ac levels in metaphase. Next, we performed ChIP-seq on mitotic-arrested cells following targeted inhibition of these histone deacetylases. We found that both HDAC2 and HDAC3 have a similar impact on H3K9ac, and inhibiting either of these two HDACs substantially increases the levels of this histone acetylation in promoters, enhancers, and insulators. Altogether, our results support a model in which H3K9 deacetylation is a stepwise process-at prophase, HDAC2 modulates most transcription-associated H3K9ac-marked loci, and at metaphase, HDAC3 maintains the reduced acetylation, whereas SIRT1 potentially regulates H3K9ac by impacting HAT activity.

Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF).

BACKGROUND: Multiple murine models of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) have been established by using obesogenic diets and/or chemical induction. MS-NASH mouse (formally FATZO) is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed a western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl4) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse. METHODS: Male MS-NASH mice at 8 weeks of age were fed WDF for the entire study. Starting at 16 weeks of age, CCl4 was intraperitoneally administered twice weekly at a dose of 0.2 mL/kg for 3 weeks or 0.08 mL/kg for 8 weeks. Obeticholic acid (OCA, 30 mg/kg, QD) was administered in both MS-NASH and C57Bl/6 mice fed WDF and treated with CCl4 (0.08 mL/kg). RESULTS: WDF enhanced obesity and hepatosteatosis, as well as induced moderate fibrosis in MS-NASH mice similar to previous reports. Administration of CCl4 accelerated liver fibrosis with increased bridging and liver hydroxyproline contents, but had no significant impact on liver steatosis and lipid contents. High dose CCl4 caused high mortality and dramatic elevation of ALT and ASL, while low dose CCl4 resulted in a moderate elevation of ALT and AST with low mortality. Compared to C57BI/6 mice with WDF and CCl4 (0.08 mL/kg), MS-NASH mice had more prominent hepatosteatosis and fibrosis. OCA treatment significantly lowered liver triglycerides, steatosis and fibrosis in both MS-NASH and C57Bl/6 mice fed WDF with CCl4 treatment. CONCLUSIONS: CCl4 reduced induction time and exacerbated liver fibrosis in MS-NASH mice on WDF, proving a superior NASH model with more prominent liver pathology, which has been used favorably in pharmaceutical industry for testing novel NASH therapeutics.

Factors that influence evidence-based program sustainment for family support providers in child protection services in disadvantaged communities.

This paper evaluates program, workplace and process factors associated with implementation and sustainment of an evidence-based parenting support program (EBP) in disadvantaged communities. Correlation analyses and binary logistic regressions were used to assess the associations between key implementation support factors and program implementation (at 18 months) and sustainment (at 36 months) post training with (N=35) Australian Aboriginal and Torres Strait Islander family support providers using the Triple P - Positive Parenting Program in Indigenous child protection agencies. This study demonstrated that for implementation at 18 months, there was a trend for implementing providers to report higher levels of partnership support, perceived program benefit, workplace support and workplace cohesion. However, the only significant relationship was with partnership support (r=.31 p<0.05), and regression analysis indicated that none of the variables were significant predictors of program implementation. For sustained implementation at 36 months, no relationship was found between sustainment and program characteristics, workplace characteristics, supervision and peer support or sustainability planning. Supportive coaching was the only significant correlate (r=0.46, p<0.01) and predictor [OR=15.63, 95% CI (1.98-123.68), p=0.009] in the program sustainment model. Overall, these findings suggest the need for further exploration of program and workplace variables and provide evidence to consider incorporating partnership support and supportive coaching in real world implementation models to improve the likelihood of EBP implementation and sustainment in Indigenous communities.

Sustained Implementation Support Scale: Validation of a Measure of Program Characteristics and Workplace Functioning for Sustained Program Implementation.

An evaluation measure of enablers and inhibitors to sustained evidence-based program (EBP) implementation may provide a useful tool to enhance organizations' capacity. This paper outlines preliminary validation of such a measure. An expert informant and consumer feedback approach was used to tailor constructs from two existing measures assessing key domains associated with sustained implementation. Validity and reliability were evaluated for an inventory composed of five subscales: Program benefits, Program burden, Workplace support, Workplace cohesion, and Leadership style. Exploratory and confirmatory factor analysis with a sample of 593 Triple P-Positive Parenting Program-practitioners led to a 28-item scale with good reliability and good convergent, discriminant, and predictive validity. Practitioners sustaining implementation at least 3 years post-training were more likely to have supervision/peer support, reported higher levels of program benefit, workplace support, and positive leadership style, and lower program burden compared to practitioners who were non-sustainers.

Sustained Implementation of Evidence-based Programs in Disadvantaged Communities: A Conceptual Framework of Supporting Factors.

This paper presents a review of the empirical literature for studies evaluating factors that facilitate and create barriers to sustained program implementation in disadvantaged communities. It outlines study methodology and sustainment outcomes and proposes a conceptual model that involves implementation sustainment support for providers delivering evidence-based health and family services in disadvantaged communities. Sustained program implementation in the community setting is a significant issue as only 43% of studies reported successfully sustained programs. The review identified 18 factors that facilitate success and create barriers to program sustainment. The factors are synthesized into three themes; program characteristics, workplace capacity, and process and interaction factors. The majority of factors map onto commonly cited sustainability influences in implementation science. However, there was an additional focus for studies included in this review on the importance of factors such as program burden, program familiarity and perceived competence in program skills, workplace support for the program, staff mobility and turnover, supervision and peer support, and ongoing technical assistance. The need to use a conceptual framework and develop measures to guide and evaluate capacity building in EBP implementation and sustainment in low-resource community settings is highlighted.