Substituted Anthraquinones Represent a Potential Scaffold for DNA Methyltransferase 1-Specific Inhibitors

In humans, the most common epigenetic DNA modification is methylation of the 5-carbon of cytosines, predominantly in CpG dinucleotides. DNA methylation is an important epigenetic mark associated with gene repression. Disruption of the normal DNA methylation pattern is known to play a role in the initiation and progression of many cancers. DNA methyltransferase 1 (DNMT1), the most abundant DNA methyltransferase in humans, is primarily responsible for maintenance of the DNA methylation pattern and is considered an important cancer drug target. Recently, laccaic acid A (LCA), a highly substituted anthraquinone natural product, was identified as a direct, DNA-competitive inhibitor of DNMT1. Here, we have successfully screened a small library of simplified anthraquinone compounds for DNMT1 inhibition. Using an endonuclease-coupled DNA methylation assay, we identified two anthraquinone compounds, each containing an aromatic substituent, that act as direct DNMT1 inhibitors. These simplified anthraquinone compounds retain the DNA-competitive mechanism of action of LCA and exhibit some selectivity for DNMT1 over DNMT3a. The newly identified compounds are at least 40-fold less potent than LCA, but have significantly less complex structures. Collectively, this data indicates that substituted anthraquinone compounds could serve as a novel scaffold for developing DNMT1-specific inhibitors

Pathways to Care of Maine Youth with Psychosis

Study clinicians conducted semi-structured interviews to identify the timing and steps of each person’s Pathway to Care (PtC).https://knowledgeconnection.mainehealth.org/lambrew-retreat-2023/1028/thumbnail.jp

IMF Reforms: Issues for Congress

This report provides information about the reforms made by the Board of Governors of the International Monetary Fund (IMF) in December 2010, Congress's role in the reform process, and how the reforms could affect U.S. interests at the IMF

IMF Reforms: Issues for Congress

Report that provides information about the reforms made by the Board of Governors of the International Monetary Fund (IMF) in December 2010, Congress's role in the reform process, and how the reforms could affect U.S. interests at the IMF

Multilateral Development Banks: How the United States Makes and Implements Policy

This report analyzes how the United States makes policy towards the multilateral development banks (MDBs) and identifies ways by which Congress can shape U.S. policy and influence the activities of the banks themselves

Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.

OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted

Crossover of Organizational Commitment

Spousal commitment toward an employee\u27s organization is a little-studied construct that deserves attention because his or her spouse may influence the employee\u27s assessments of organizational commitment and turnover intentions. Using 186 couples, this study investigated spousal influence on U.S. military members’ organizational commitment and their decisions to reenlist. Results of a structural equation model analysis indicate that indirect mechanisms of crossover (e.g., positive emotions displayed by the spouse during discussions of reenlistment) facilitated the positive relationships between the organizational commitment of military spouses and members. Findings and discussion contribute to the fields of organizational commitment and crossover, and we conclude our analysis by offering practical implications for nonmilitary occupations

HIV Combination Prevention study - Data at months 0, 9 and 15

Dataset and supporting documentation collected as part of the HIV combination prevention study, a cluster randomised trial investigating the feasibility of conducting HIV combination prevention interventions in fishing communities in Uganda. The dataset contains participant-provided responses including condom use, HIV prevention practices, and intervention take-up

A Sport-Based Intervention to Increase Uptake of Voluntary Medical Male Circumcision Among Adolescent Male Students: Results From the MCUTS 2 Cluster-Randomized Trial in Bulawayo, Zimbabwe.

BACKGROUND: Mathematical models suggest that 570,000 HIV infections could be averted between 2011 and 2025 in Zimbabwe if the country reaches 80% voluntary medical male circumcision (VMMC) coverage among 15- to 49-year-old male subjects. Yet national coverage remains well below this target, and there is a need to evaluate interventions to increase the uptake. METHODS: A cluster-randomized trial was conducted to assess the effectiveness of Make-The-Cut-Plus (MTC+), a single, 60-minute, sport-based intervention to increase VMMC uptake targeting secondary school boys (14-20 years). Twenty-six schools in Bulawayo, Zimbabwe, were randomized to either receive MTC+ at the start (intervention) or end (control) of a 4-month period (March to June 2014). VMMC uptake over these 4 months was measured via probabilistic matching of participants in the trial database (n = 1226 male participants; age, 14-20 years; median age, 16.2 years) and the registers in Bulawayo's 2 free VMMC clinics (n = 5713), using 8 identifying variables. RESULTS: There was strong evidence that the MTC+ intervention increased the odds of VMMC uptake by approximately 2.5 fold (odds ratio = 2.53; 95% confidence interval, 1.21 to 5.30). Restricting to participants who did not report being already circumcised at baseline, MTC+ increased VMMC uptake by 7.6% (12.2% vs 4.6%, odds ratio = 2.65; 95% confidence interval, 1.19 to 5.86). Sensitivity analyses related to the probabilistic matching did not change these findings substantively. The number of participants who would need to be exposed to the demand creation intervention to yield one additional VMMC client was 22.7 (or 13.2 reporting not already being circumcised). This translated to approximately US dollar 49 per additional VMMC client. CONCLUSIONS: The MTC+ intervention was an effective and cost-effective strategy for increasing VMMC uptake among school-going adolescent male subjects in Bulawayo

Feasibility of conducting HIV combination prevention interventions in fishing communities in Uganda : A pilot cluster randomised trial

Objective We assessed feasibility of an HIV-combination-prevention trial among fishing communities in Uganda. Design Cluster randomised trial in four fishing communities on Lake Victoria, Uganda. Two intervention communities received a combination-prevention-package (behaviour change communication, condom promotion, HIV testing, voluntary male medical circumcision and referral for anti-retroviral therapy if HIV-positive). All four communities received routine government HIV care services. Methods Using household census data we randomly selected a cohort of consenting residents aged 18 years. A baseline sero-survey in July 2014 was followed by two repeat surveys in March and December 2015. We measured uptake of HIV prevention methods, loss-to-follow-up and HIV incidence, accounting for multistage survey design. Results A total of 862 participants were enrolled and followed for 15 months. Participation was 62% and 74% in the control and intervention arms respectively; Overall loss to follow up (LTFU) was 21.6% and was similar by arm. Self-reported abstinence/faithfulness increased between baseline and endline in both arms from 53% to 73% in the control arm, and 55% to 67% in the intervention arm. Reported condom use throughout the study period was 36% in the intervention arm vs 28% in the control arm; number of male participants reporting cir-cumsicion in both arms from 58% to 79% in the intervention arm, and 39% to 46% in the control arm. Independent baseline predictors of loss-to-follow-up were: being HIV positive, residence in the community for 1 month/year Conclusions Recruitment and retention of participants in longitudinal trials in highly mobile HIV fishing communities is challenging. Future research should investigate modes for locating and retaining participants, and delivery of HIV-combination prevention