Sirtuins catalyze NAD+-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1–7), and SIRT1 has been ...implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
Studies in the fruit fly
Drosophila melanogaster and the nematode
Caenorhabditis elegans have revealed that components of the insulin signaling pathway have been highly conserved during evolution. ...Genetic analysis in
Drosophila suggests that structural conservation also extends to the functional level. Flies carrying mutations that reduce insulin signaling have a growth deficiency phenotype similar to that seen in mice with disruptions of genes encoding insulin-like growth factors (IGFs) or the IGF-I receptor. Recent studies in flies have demonstrated a role for the insulin signaling pathway in the regulation of metabolism, reproduction and lifespan via modulation of central neuroendocrine pathways. Similarly, mice with loss of brain insulin receptors or insulin receptor substrate 2 deficiency exhibit neuroendocrine defects and female infertility. These parallels suggest that the insulin system has multiple conserved roles, acting directly to modulate growth and indirectly, via the neuroendocrine system, to modulate peripheral physiology in response to changes in nutrient availability.
Studies in the fruit fly and the nematode have revealed that components of the insulin signaling pathway have been highly conserved during evolution. Genetic analysis in Drosophila suggests that structural conservation also extends to the functional level.
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•As usability factors are closely linked to the success or failure of the technology, it is important to assess the usability of the technology during system development.•Eye-tracking ...has the potential to improve usability assessments by providing valuable ocular data.•We presented a novel methodological approach of an eye-tracking retrospective think-aloud for usability evaluation and described its application in assessing the usability of a mobile health app.•An eye-tracking retrospective think-aloud enabled us to identify critical usability problems and gain an in-depth understanding of the usability issues related to interactions between end-users and the app.
To report on the use of an eye-tracking retrospective think-aloud for usability evaluation and to describe its application in assessing the usability of a mobile health app.
We used an eye-tracking retrospective think-aloud to evaluate the usability of an HIV prevention mobile app among 20 young men (15–18 years) in New York City, NY; Birmingham, AL; and Chicago, IL. Task performance metrics, critical errors, a task completion rate per participant, and a task completion rate per task, were measured. Eye-tracking metrics including fixation, saccades, time to first fixation, time spent, and revisits were measured and compared among participants with/without a critical error.
Using task performance analysis, we identified 19 critical errors on four activities, and of those, two activities had a task completion rate of less than 78%. To better understand these usability issues, we thoroughly analyzed participants’ corresponding eye movements and verbal comments using an in-depth problem analysis. In areas of interest created for the activity with critical usability problems, there were significant differences in time spent (p = 0.008), revisits (p = 0.004), and total numbers of fixations (p = 0.007) by participants with/without a critical error. The overall mean score of perceived usability rated by the Health IT Usability Evaluation Scale was 4.64 (SD = 0.33), reflecting strong usability of the app.
An eye-tracking retrospective think-aloud enabled us to identify critical usability problems as well as gain an in-depth understanding of the usability issues related to interactions between end-users and the app. Findings from this study highlight the utility of an eye-tracking retrospective think-aloud in consumer health usability evaluation research.
For youth living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), nonadherence to antiretroviral therapy (ART) can lead to poor health outcomes and significantly ...decreased life expectancy.
To evaluate the feasability, acceptability, and preliminary efficacy of short message service (SMS) or text message reminders to improve adherence to ART for youth living with HIV/AIDS.
We conducted this prospective pilot study using a pre-post design from 2009 to 2010 at a community-based health center providing clinical services to youth living with HIV/AIDS. Eligibility criteria included HIV-positive serostatus, age 14-29 years, use of a personal cell phone, English-speaking, and being on ART with documented poor adherence. During the 24-week study period, participants received personalized daily SMS reminders and a follow-up message 1 hour later assessing whether they took the medication, and asking participants to respond via text message with the number 1 if they took the medication and 2 if they did not. Outcome measures were feasibility, acceptability, and adherence. Self-reported adherence was determined using the visual analog scale (VAS) and AIDS Clinical Trial Group (ACTG) questionnaire 4-day recall. Viral load and CD4 cell count were followed as biomarkers of adherence and disease progression at 0, 12, and 24 weeks.
Participants (N = 25) were mean age 23 (range 14-29) years, 92% (n = 23) male, 60% (n = 15) black, and 84% (n = 21) infected through unprotected sex. Mean VAS scores significantly increased at 12 and 24 weeks in comparison with baseline (week 0: 74.7, week 12: 93.3, P < .001; week 24: 93.1, P < .001). ACTG questionnaire 4-day recall also improved (week 0: 2.33, week 12: 3.24, P = .002; week 24: 3.19, P = .005). There was no significant difference in CD4 cell count or viral load between baseline and 12- or 24-week follow-up, although there was a trend toward improvement of these biomarkers and a small to moderate standardized effect size (range of Cohen d: -0.51 to 0.22). Of 25 participants, 21 (84%) were retained, and 20 of the 21 (95%) participants who completed the study found the intervention helpful to avoid missing doses.
In this pilot study, personalized, interactive, daily SMS reminders were feasible and acceptable, and they significantly improved self-reported adherence. Larger controlled studies are needed to determine the impact of this intervention on ART adherence and other related health outcomes for youth living with HIV/AIDS.
Abstract Purpose Very few studies have examined mental disorders among male sexual minority youth. We describe demographic correlates, comorbidity, and history of mental disorders and suicidality in ...a large sample of male sexual minority youth. Methods Structured diagnostic interviews were conducted with 449 racially diverse urban sexual minority males, aged 16–20 years, who were recruited using a social network–driven sampling methodology. Results Lifetime major depressive episode (MDE) affected 33.2% of the youth. Lifetime conduct disorder (23.6%), alcohol abuse/dependence (19.6%), posttraumatic stress disorder (PTSD; 16.0%), and nicotine dependence (10.7%) were also common. Black participants were less likely than white participants to be diagnosed with lifetime MDE, alcohol abuse/dependence, nicotine dependence, suicidal ideation, and anorexia, as well as past 12-month alcohol abuse/dependence (odds ratios ORs range from .08 to .46). Relative to participants identifying as gay, bisexual identified youth were at higher risk for lifetime PTSD (OR = 2.04), and participants who did not identify as gay or bisexual were at higher risk for both lifetime and past 12-month nicotine dependence (OR = 4.36 and 3.46, respectively). Most participants with mental disorders never received treatment, and comorbidity was common. Conclusions MDE, conduct disorder, alcohol abuse/dependence, PTSD, and nicotine dependence are common and infrequently treated in young sexual minority men. Some within-group disparities emerged, suggesting that factors related to racial background and self-identification may help to understand resilience to the unique stressors experienced by these young men.
Transgender women in the U.S. have an alarmingly high incidence rate of HIV infection; condomless anal and vaginal sex is the primary risk behavior driving transmission. Young transgender women are ...the subpopulation at the highest risk for HIV. Despite this, there are no published randomized controlled efficacy trials testing interventions to reduce sexual risk for HIV among this group. This paper describes the design of a group-based intervention trial to reduce sexual risk for HIV acquisition and transmission in young transgender women.
This study, funded by the National Institutes of Health, is a randomized controlled trial of a culturally-specific, empowerment-based, and group-delivered six-session HIV prevention intervention, Project LifeSkills, among sexually active young transgender women, ages 16-29 years in Boston and Chicago. Participants are randomized (2:2:1) to either the LifeSkills intervention, standard of care only, or a diet and nutrition time- and attention-matched control. At enrollment, all participants receive standardized HIV pre- and post-test counseling and screening for HIV and urogenital gonorrhea and chlamydia infections. The primary outcome is difference in the rate of change in the number of self-reported condomless anal or vaginal sex acts during the prior 4-months, assessed at baseline, 4-, 8-, and 12-month follow-up visits.
Behavioral interventions to reduce sexual risk for HIV acquisition and transmission are sorely needed for young transgender women. This study will provide evidence to determine feasibility and efficacy in one of the first rigorously designed trials for this population.
ClinicalTrials.gov number, NCT01575938 , registered March 29, 2012.
Young sexual minority men in the United States have a high incidence rate of HIV infection. Early intervention among this group, that is timed to precede or coincide with sexual initiation, is of ...critical importance to prevent HIV infection. Despite this, there are very few published randomized controlled efficacy trials testing interventions to reduce sexual vulnerability for HIV acquisition among racially/ethnically diverse, very young, sexual minority men (aged ≤18 years). This paper describes the design of a mobile app-based intervention trial to reduce sexual risk for HIV acquisition and promote health protection in this group.
This study is a randomized controlled trial of an mHealth-based HIV prevention intervention, MyPEEPS Mobile, among diverse sexual minority cisgender young men, aged 13-18 years. The mobile intervention was adapted from a prior group-based intervention curriculum with evidence of efficacy, designed to be specific to the risk contexts and realities of young sexual minority men, and to include psychoeducational and skill-building components with interactive games and activities. Participants are recruited locally within four regional hubs (Birmingham, AL, Chicago, IL, New York City, NY, Seattle, WA) and nationwide via the Internet, enrolled in-person or remotely (via videoconference), and randomized (1:1) to either the MyPEEPS Mobile intervention or delayed intervention condition. Post-hoc stratification by age, race/ethnicity, and urban/suburban vs. rural statuses is used to ensure diversity in the sample. The primary outcomes are number of male anal sex partners and frequency of sexual acts with male partners (with and without condoms), sex under the influence of substances, and uptake of pre-and post-exposure prophylaxis, as well as testing for HIV and other sexually transmitted infections at 3-, 6- and 9-month follow-up.
Behavioral interventions for very young sexual minority men are needed to prevent sexual risk early in their sexual development and maturation. This study will provide evidence to determine feasibility and efficacy of a mobile app-based HIV prevention intervention to reduce sexual risk among this very young group.
ClinicalTrials.gov number, NCT03167606, registered May 30, 2017.
A high-resolution time series of transcript abundance was generated to describe global expression dynamics in response to nutrition in Drosophila. Nonparametric change-point statistics revealed that ...within 7 h of feeding upon yeast, transcript levels changed significantly for approximately 3,500 genes or 20% of the Drosophila genome. Differences as small as 15% were highly significant, and 80% of the changes were <1.5-fold. Notably, transcript changes reflected rapid downregulation of the nutrient-sensing insulin and target of rapamycin pathways, shifting of fuel metabolism from lipid to glucose oxidation, and increased purine synthesis, TCA-biosynthetic functions and mitochondria biogenesis. To investigate how nutrition coordinates these transcriptional changes, feeding-induced expression changes were compared with those induced by the insulin-regulated transcription factor dFOXO in Drosophila S2 cells. Remarkably, 28% (995) of the nutrient-responsive genes were regulated by activated dFOXO, including genes of mitochondrial biogenesis and a novel homolog of mammalian peroxisome proliferator-gamma coactivator-1 (PGC-1), a transcriptional coactivator implicated in controlling mitochondrial gene expression in mammals. These data implicate dFOXO as a major coordinator of the transcriptional response to nutrients downstream of insulin and suggest that mitochondria biogenesis is linked to insulin signaling via dFOXO-mediated repression of a PGC-1 homolog.
Abstract We examined the potential for a family-based HIV prevention approach for gay and bisexually identified young men who have sex with men (MSM). The majority of our urban, ethnically diverse ...sample disclosed their sexual orientation to parents, who were generally supportive. Family connectedness significantly decreased the odds of an HIV positive status.
Transgender men and transmasculine youth are at high risk for acquiring HIV. Growing research on transgender men demonstrates increased HIV risk and burden compared with the general US population. ...Despite biomedical advancements in HIV prevention, there remains a dearth of evidence-based, sexual health HIV prevention interventions for young transgender men. MyPEEPS (Male Youth Pursuing Empowerment, Education, and Prevention around Sexuality) Mobile is a web-based app that builds on extensive formative community-informed work to develop an evidence-based HIV prevention intervention. Our study team developed and tested the MyPEEPS Mobile intervention for 13- to 18-year-old cisgender young men in a national randomized controlled trial, which demonstrated efficacy to reduce sexual risk in the short term-at 3-month follow-up. Trans men and transmasculine youth resonated with basic HIV educational information and sexual scenarios of the original MyPEEPS app for cisgender men, but recognized the app's lack of transmasculine specificity.
The purpose of this study is to detail the user-centered design methods to adapt, improve the user interface, and enhance the usability of the MyPEEPS Mobile app for young transgender men and transmasculine youth.
The MyPEEPS Mobile app for young transgender men was adapted through a user-centered design approach, which included an iterative review of the adapted prototype by expert advisors and a youth advisory board. The app was then evaluated through a rigorous usability evaluation.
MyPEEPS Mobile is among the first mobile health interventions developed to meet the specific needs of young transgender men and transmasculine youth to reduce HIV risk behaviors. While many of the activities in the original MyPEEPS Mobile were rigorously developed and tested, there was a need to adapt our intervention to meet the specific needs and risk factors among young transgender men and transmasculine youth. The findings from this study describe the adaptation of these activities through feedback from a youth advisory board and expert advisors. Following adaptation of the content, the app underwent a rigorous usability assessment through an evaluation with experts in human-computer interaction (n=5) and targeted end users (n=20).
Usability and adaptation findings demonstrate that the MyPEEPS Mobile app is highly usable and perceived as potentially useful for targeting HIV risk behaviors in young transgender men and transmasculine youth.
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