Membrane lipid-modulated mechanism of action and non-cytotoxicity of novel fungicide aminoglycoside FG08

A novel aminoglycoside, FG08, that differs from kanamycin B only by a C8 alkyl chain at the 4″-O position, was previously reported. Unlike kanamycin B, FG08 shows broad-spectrum fungicidal but not anti-bacterial activities. To understand its specificity for fungi, the mechanism of action of FG08 was studied using intact cells of the yeast Saccharomyces cerevisiae and small unilamellar membrane vesicles. With exposure to FG08 (30 µg mL−1), 8-fold more cells were stained with fluorescein isothiocyanate, cells had 4 to 6-fold higher K+ efflux rates, and 18-fold more cells were stained with SYTOX Green in comparison to exposure to kanamycin B (30 µg mL−1). Yeast mutants with aberrant membrane sphingolipids (no sphingoid base C4 hydroxyl group, truncated very long fatty acid chain, or lacking the terminal phosphorylinositol group of mannosyl-diinositolphosphorylphytoceramide were 4 to 8-fold less susceptible to growth inhibition with FG08 and showed 2 to 10-fold lower SYTOX Green dye uptake rates than did the isogenic wild-type strain. FG08 caused leakage of pre-loaded calcein from 50% of small unilamellar vesicles with glycerophospholipid and sterol compositions that mimic the compositions of fungal plasma membranes. Less than 5 and 10% of vesicles with glycerophospholipid and sterol compositions that mimic bacterial and mammalian cell plasma membranes, respectively, showed calcein leakage. In tetrazolium dye cytotoxicity tests, mammalian cell lines NIH3T3 and C8161.9 showed FG08 toxicity at concentrations that were 10 to 20-fold higher than fungicidal minimal inhibitory concentrations. It is concluded that FG08’s growth inhibitory specificity for fungi lie in plasma membrane permeability changes involving mechanisms that are modulated by membrane lipid composition

Implementation-effectiveness trial of an ecological intervention for physical activity in ethnically diverse low income senior centers.

BackgroundAs the US population ages, there is an increasing need for evidence based, peer-led physical activity programs, particularly in ethnically diverse, low income senior centers where access is limited.Methods/designThe Peer Empowerment Program 4 Physical Activity' (PEP4PA) is a hybrid Type II implementation-effectiveness trial that is a peer-led physical activity (PA) intervention based on the ecological model of behavior change. The initial phase is a cluster randomized control trial randomized to either a peer-led PA intervention or usual center programming. After 18 months, the intervention sites are further randomized to continued support or no support for another 6 months. This study will be conducted at twelve senior centers in San Diego County in low income, diverse communities. In the intervention sites, 24 peer health coaches and 408 adults, aged 50 years and older, are invited to participate. Peer health coaches receive training and support and utilize a tablet computer for delivery and tracking. There are several levels of intervention. Individual components include pedometers, step goals, counseling, and feedback charts. Interpersonal components include group walks, group sharing and health tips, and monthly celebrations. Community components include review of PA resources, walkability audit, sustainability plan, and streetscape improvements. The primary outcome of interest is intensity and location of PA minutes per day, measured every 6 months by wrist and hip accelerometers and GPS devices. Secondary outcomes include blood pressure, physical, cognitive, and emotional functioning. Implementation measures include appropriateness & acceptability (perceived and actual fit), adoption & penetration (reach), fidelity (quantity & quality of intervention delivered), acceptability (satisfaction), costs, and sustainability.DiscussionUsing a peer led implementation strategy to deliver a multi-level community based PA program can enhance program adoption, implementation, and sustainment.Trial registrationClinicalTrials.gov, USA ( NCT02405325 ). Date of registration, March 20, 2015. This website also contains all items from the World Health Organization Trial Registration Data Set

Two-Arm Randomized Pilot Intervention Trial to Decrease Sitting Time and Increase Sit-To-Stand Transitions in Working and Non-Working Older Adults.

BACKGROUND: Excessive sitting has been linked to poor health. It is unknown whether reducing total sitting time or increasing brief sit-to-stand transitions is more beneficial. We conducted a randomized pilot study to assess whether it is feasible for working and non-working older adults to reduce these two different behavioral targets. METHODS: Thirty adults (15 workers and 15 non-workers) age 50-70 years were randomized to one of two conditions (a 2-hour reduction in daily sitting or accumulating 30 additional brief sit-to-stand transitions per day). Sitting time, standing time, sit-to-stand transitions and stepping were assessed by a thigh worn inclinometer (activPAL). Participants were assessed for 7 days at baseline and followed while the intervention was delivered (2 weeks). Mixed effects regression analyses adjusted for days within participants, device wear time, and employment status. Time by condition interactions were investigated. RESULTS: Recruitment, assessments, and intervention delivery were feasible. The 'reduce sitting' group reduced their sitting by two hours, the 'increase sit-to-stand' group had no change in sitting time (p < .001). The sit-to-stand transition group increased their sit-to-stand transitions, the sitting group did not (p < .001). CONCLUSIONS: This study was the first to demonstrate the feasibility and preliminary efficacy of specific sedentary behavioral goals. TRIAL REGISTRATION: clinicaltrials.gov NCT02544867.The pilot study was supported by funds provided by the Department of Family Medicine & Public Health, UCSD. The work of Andrew J Atkin was supported by the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence (RES-590-28-0002). Funding from the British Heart Foundation, Department of Health, Economic and Social Research Council, Medical Research Council, and the Wellcome Trust, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It was first available from PLOS via http://dx.doi.org/10.1371/journal.pone.014542

Associations of recreational and non-recreational physical activity with coronary artery calcium density vs. volume and cardiovascular disease events: the Multi-Ethnic Study of Atherosclerosis.

AimsThe benefits of physical activity (PA) on cardiovascular disease (CVD) are well known. However, studies suggest PA is associated with coronary artery calcium (CAC), a subclinical marker of CVD. In this study, we evaluated the associations of self-reported recreational and non-recreational PA with CAC composition and incident CVD events. Prior studies suggest high CAC density may be protective for CVD events.Methods and resultsWe evaluated 3393 participants of the Multi-Ethnic Study of Atherosclerosis with prevalent CAC. After adjusting for demographics, the highest quintile of recreational PA was associated with 0.07 (95% confidence interval 0.01-0.13) units greater CAC density but was not associated with CAC volume. In contrast, the highest quintile of non-recreational PA was associated with 0.08 (0.02-0.14) units lower CAC density and a trend toward 0.13 (-0.01 to 0.27) log-units higher CAC volume. There were 520 CVD events over a 13.7-year median follow-up. Recreational PA was associated with lower CVD risk (hazard ratio 0.88, 0.79-0.98, per standard deviation), with an effect size that was not changed with adjustment for CAC composition or across levels of prevalent CAC.ConclusionRecreational PA may be associated with a higher density but not a higher volume of CAC. Non-recreational PA may be associated with lower CAC density, suggesting these forms of PA may not have equivalent associations with this subclinical marker of CVD. While PA may affect the composition of CAC, the associations of PA with CVD risk appear to be independent of CAC

Antifungal amphiphilic aminoglycoside K20: bioactivities and mechanism of action

K20 is a novel amphiphilic antifungal aminoglycoside that is synthetically derived from the antibiotic kanamycin A. Reported here are investigations of K20′s antimicrobial activities, cytotoxicity, and fungicidal mechanism of action. In vitro growth inhibitory activities against a variety of human and plant pathogenic yeasts, filamentous fungi, and bacteria were determined using microbroth dilution assays and time-kill curve analyses, and hemolytic and animal cell cytotoxic activities were determined. Effects on Cryptococcus neoformans H-99 infectivity were determined with a preventive murine lung infection model. The antifungal mechanism of action was studied using intact fungal cells, yeast lipid mutants, and small unilamellar lipid vesicles. K20 exhibited broad-spectrum in vitro antifungal activities but not antibacterial activities. Pulmonary, single dose-administration of K20 reduced C. neoformans lung infection rates 4-fold compared to controls. Hemolysis and half-maximal cytotoxicities of mammalian cells occurred at concentrations that were 10 to 32-fold higher than fungicidal MICs. With fluorescein isothiocyanate (FITC), 20–25 mg/L K20 caused staining of \u3e95% of C. neoformans and Fusarium graminearum cells and at 31.3 mg/L caused rapid leakage (30–80% in 15 min) of calcein from preloaded small unilamellar lipid vesicles. K20 appears to be a broad-spectrum fungicide, capable of reducing the infectivity of C. neoformans, and exhibits low hemolytic activity and mammalian cell toxicity. It perturbs the plasma membrane by mechanisms that are lipid modulated. K20 is a novel amphiphilic aminoglycoside amenable to scalable production and a potential lead antifungal for therapeutic and crop protection applications

Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154620/1/fsb2fj201700349r.pd

Take a Stand: A Mixed Methods Approach to Evaluate a Pilot Sedentary Behavior Intervention

Background: Society is sitting more than ever before. Large-scale epidemiological evidence indicates that prolonged sitting time has negative health impacts including increased risk of metabolic syndrome, heart disease, weight gain, cancer, and premature mortality. Older adults are an important population to target because they represent the most sedentary segment of the population who struggle to meet activity guidelines. Based on these negative health associations, research on sedentary behavior interventions, especially focused on older adults, is a public health priority. Methods: This dissertation uses data from a pilot sedentary behavior intervention in 30 adults aged 50-70 years to understand how to measure and prompt sedentary behavior change. The intervention successfully targeted two distinct sitting interruption modalities (i.e., sit less, increase sit-to-stand transitions). Chapter 1 explored differences in self-reported and objectively-measured sitting time to evaluate participants’ ability to self-assess behavior during an intervention. Chapter 2 included a mixed methods analysis of tool use to disrupt sitting time during the pilot intervention. Chapter 3 used focus groups to explore participants’ perceptions regarding wearable devices to track and change sedentary behavior.Results: Chapter 1 found significant differences in self-reported sitting time by day of week, employment status, and participation in a sedentary behavior intervention. Chapter 2 showed that participants who used effective tools were most successful in reducing sitting time. In contrast, current tools for increasing sit-to-stand transitions were ineffective. The focus groups from Chapter 3 revealed that participants were amenable to using wearable devices; however, current devices lack key features necessary for sedentary behavior including the ability to accurately measure sitting time and distinguish “inactivity” from standing.Discussion: Given the negative health outcomes associated with excessive sitting, more interventions are targeting sedentary behavior. The three themes explored in this dissertation (specificity of measurement, tools, and behaviors) and the combination of analysis methods help increase our understanding of sedentary behavior in older adults. This dissertation provides recommendations to improve the field by using specific measures for sitting time to capture differences across the week, designing interventions to include tools with a specific focus on sedentary behavior, and exploring how technology can help change behavior

Relationship between Objectively Measured Transportation Behaviors and Health Characteristics in Older Adults

This study used objective Global Positioning Systems (GPS) to investigate the relationship between pedestrian and vehicle trips to physical, cognitive, and psychological functioning in older adults living in retirement communities. Older adults (N = 279; mean age = 83 ± 6 years) wore a GPS and accelerometer for 6 days. Participants completed standard health measures. The Personal Activity and Location Measurement System (PALMS) was used to calculate the average daily number of trips, distance, and minutes traveled for pedestrian and vehicle trips from the combined GPS and accelerometer data. Linear mixed effects regression models explored relationships between these transportation variables and physical, psychological and cognitive functioning. Number, distance, and minutes of pedestrian trips were positively associated with physical and psychological functioning but not cognitive functioning. Number of vehicle trips was negatively associated with fear of falls; there were no other associations between the vehicle trip variables and functioning. Vehicle travel did not appear to be related to functioning in older adults in retirement communities except that fear of falling was related to number of vehicle trips. Pedestrian trips had moderate associations with multiple physical and psychological functioning measures, supporting a link between walking and many aspects of health in older adults

Using Fluorogenic Probes for the Investigation of Selective Biomass Degradation by Fungi

A library of fifteen commercially purchased and synthetic fluorogenic probes was employed for the investigation of biomass degradation using extracts of white-rot fungi. These probes were selected or designed to mimic the dominant linkages in celluloses, hemicelluloses, and lignin, the three most abundant polymers found in biomass. The results show that white-rot fungi display a high preference for cleaving mannose- and glucose-based probes, which mimic hemicelluloses. Low degrees of cleavages were noted for xylose- and cellobiose-based probes. No cleavages were observed for probes that mimic the linkages in lignin. Overall, these discoveries prove that it is possible to employ fungi for selective degradation or release of hemicelluloses from biomass

Diet and Activity Assessments and Interventions Using Technology in Older Adults.

UNLABELLED: This paper reports on the findings and recommendations specific to older adults from the Tech Summit: Innovative Tools for Assessing Diet and Physical Activity for Health Promotion forum organized by the North American branch of the International Life Sciences Institute. The summit aimed to investigate current and emerging challenges related to improving energy balance behavior assessment and intervention via technology. The current manuscript focuses on how novel technologies are applied in older adult populations and enumerated the barriers and facilitators to using technology within this population. Given the multiple applications for technology in this population, including the ability to monitor health events and behaviors in real time, technology presents an innovative method to aid with the changes associated with aging. Although older adults are often perceived as lacking interest in and ability to adopt technologies, recent studies show they are comfortable adopting technology and user uptake is high with proper training and guided facilitation. Finally, the conclusions suggest recommendations for future research, including the need for larger trials with clinical outcomes and more research using end-user design that includes older adults as technology partners who are part of the design process. THEME INFORMATION: This article is part of a theme issue entitled Innovative Tools for Assessing Diet and Physical Activity for Health Promotion, which is sponsored by the North American branch of the International Life Sciences Institute