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ABSTRACT IMPACT: The key to advancing precision medicine is to deepen our understanding of drug modes-of-action (MOA). This project aims to develop a novel method for predicting MOA of potential drug compounds, providing an experimental and computational platform for more efficient drug discovery. OBJECTIVES/GOALS: To develop (1) a targeted CRISPR-Cas9 chemical-genetic screen approach, and (2) a computational method to predict drug mode-of-action from chemical-genetic interaction profiles. METHODS/STUDY POPULATION: Screening drugs against a gene deletion library can identify knockouts that modulate drug sensitivity. These chemical-genetic interaction (CGI) screens can be performed in human cell lines using a pooled lentiviral CRISPR-Cas9 approach to assess drug sensitivity/resistance of single-gene knockouts across the human genome. A targeted, rather than genome-wide, library can enable scaling these screens across many drugs.
CGI profiles can be derived from phenotypic screen readouts. These profiles are analogous to genetic interaction (GI) profiles, which represent sensitivity/resistance of gene knockouts to a second gene knockout rather than a drug. To computationally predict a drug’s genetic target, we leverage the property that a drug’s CGI profile will be similar to its target’s GI profile. RESULTS/ANTICIPATED RESULTS: Five proof-of-principle screens will be conducted with compounds that have existing genome-wide profiles and well-characterized MOA. I will generate CGI profiles for these five compounds and identify genes that are drug-sensitizers or drug-suppressors. I will then evaluate whether targeted library screens can recapitulate the CGIs found in genome-wide screens. Finally, I will develop a computational tool to integrate these CGI profiles with GI profiles (derived from another project) to predict gene-level and bioprocess-level drug targets. These predictions (from both targeted and genome-wide profiles) will be benchmarked against a drug-target and drug-bioprocess standard. DISCUSSION/SIGNIFICANCE OF FINDINGS: This work will develop a scalable, targeted chemical-genetic screen approach to discovering how putative therapeutics work. The targeted screen workflow provides a method for higher-throughput drug screening. The computational pipeline provides a powerful tool for exploring the MOA of uncharacterized drugs or repurposing FDA-approved drugs.
A higher intake of food rich in flavonoids such as quercetin can reduce the risk of CVD. Enzymatically modified isoquercitrin (EMIQ®) has a bioavailability 17-fold higher than quercetin aglycone and has shown potential CVD moderating effects in animal studies. The present study aimed to determine whether acute ingestion of EMIQ® improves endothelial function, blood pressure (BP) and cognitive function in human volunteers at risk of CVD. Twenty-five participants (twelve males and thirteen females) with at least one CVD risk factor completed this randomised, controlled, crossover study. In a random order, participants were given EMIQ® (2 mg aglycone equivalent)/kg body weight or placebo alongside a standard breakfast meal. Endothelial function, assessed by flow-mediated dilatation (FMD) of the brachial artery was measured before and 1·5 h after intervention. BP, arterial stiffness, cognitive function, BP during cognitive stress and measures of quercetin metabolites, oxidative stress and markers of nitric oxide (NO) production were assessed post-intervention. After adjustment for pre-treatment measurements and treatment order, EMIQ® treatment resulted in a significantly higher FMD response compared with the placebo (1·80 (95 % CI 0·23, 3·37) %; P = 0·025). Plasma concentrations of quercetin metabolites were significantly higher (P < 0·001) after EMIQ® treatment compared with the placebo. No changes in BP, arterial stiffness, cognitive function or biochemical parameters were observed. In this human intervention study, the acute administration of EMIQ® significantly increased circulating quercetin metabolites and improved endothelial function. Further clinical trials are required to assess whether health benefits are associated with long-term EMIQ® consumption.
Invasive populations of Dalmation toadflax [Linaria dalmatica (L.) Mill.] and yellow toadflax (Linaria vulgaris Mill.) are widespread throughout the Intermountain West, where gene flow between these nonnative species is producing vigorous and fertile hybrids. These hybrid toadflax populations are less responsive to herbicides than either parent species, and biocontrol agents routinely released on L. dalmatica and L. vulgaris often fail to establish on hybrid hosts. Early detection of hybrid Linaria populations is therefore essential for effective management, but resources are limited for scouting large expanses of range and wildland. We used species distribution modeling to identify environmentally suitable areas for these invasive Linaria taxa in Montana, Wyoming, and Colorado. Areas suitable for hybrid Linaria establishment were estimated using two different modeling approaches: first, based on known hybrid occurrence and associated environmental conditions, and second, based on zones environmentally suitable for co-occurrence of the parent species. This also allowed comparison of different model outputs, especially relevant when modeling emerging invasives, such as novel hybrids, with minimal occurrence data. Combining the two model outputs identified areas at greatest risk of hybrid Linaria invasion, including parts of north-central Montana, where model estimates indicate the hybrid may spread without prior co-invasion of the parents. Potential hybrid hot spots were also identified in western Montana; northwestern, northeastern, and southeastern Wyoming; and the Western Slope and Front Range of Colorado. Despite relatively few confirmed occurrences of hybrid populations to date, our results indicate that extensive spread of hybrid populations is possible within the studied area. Model-based maps of potential Linaria distributions will allow area weed managers to direct limited resources more effectively for locating and controlling these invaders.
The onset of interfacial instability in two-fluid systems using a viscous, leaky dielectric model is studied. The instability arises as a result of resonance between the parametric frequency of an imposed electric field and the system’s natural frequency. In addition to a rigorous model that uses Floquet instability analysis, where both viscous and charge effects are considered, this study also provides convincing validating experiments. In other results, it is shown that (a) the imposition of a periodic electrostatic potential acts to counter gravity and this countering effect becomes more effective if a DC voltage is also added, (b) a critical DC voltage exists at which the interface becomes unstable such that no parametric frequency is required to completely destabilize the interface and (c) the leaky dielectric model approaches a model for a perfect dielectric/perfect conductor pair as the conductivity ratio becomes large. It is also shown via experiments that parametric resonant instability using electrostatic forcing may be reliably used to estimate interfacial tension to sufficient accuracy.
Previous reports investigating adiposity and cognitive function in the population allude to a negative association, although the relationship in older adults is unclear. The aim of this study was to investigate the association of adiposity (BMI and waist:hip ratio (WHR)) with cognitive function in community-dwelling older adults (≥60 years). Participants included 5186 adults from the Trinity Ulster Department of Agriculture ageing cohort study. Neuropsychological assessment measures included the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Multi-variable linear regression models were used to assess the association between adiposity and cognitive function adjusting for insulin resistance, inflammation and cerebrovascular disease. The mean ages were 80·3 (sd 6·7), 71·0 (sd 7·3) and 70·2 (sd 6·3) years on the cognitive, bone and hypertensive cohorts, respectively. In the cognitive cohort, BMI was positively associated with immediate and delay memory, visuospatial/constructional ability, language and MMSE, and negatively with FAB (log-transformed), whereas WHR was negatively associated with attention. In the bone cohort, BMI was not associated with any cognitive domain, whereas WHR was negatively associated with visuospatial/constructional ability, attention and MMSE. In the hypertensive cohort, BMI was not associated with any cognitive domain, whereas WHR was negatively associated with immediate and delayed memory, visuospatial/constructional ability, language and MMSE and positively with FAB (log-transformed). In the cognitive and bone cohorts, the association of WHR and attention disappeared by further controlling for C-reactive protein and HbA1C. In this study of older adults, central adiposity was a stronger predictor of poor cognitive performance than BMI. Older adults could benefit from targeted public health strategies aimed at reducing obesity and obeseogenic risk factors to avoid/prevent/slow cognitive dysfunction.
The Institute of Medicine recommended the advance of innovation and entrepreneurship training programs within the Clinical & Translational Science Award (CTSA) program; however, there remains a gap in adoption by CTSA institutes. The University of Michigan’s Michigan Institute for Clinical & Health Research and Fast Forward Medical Innovation (FFMI) partnered to develop a pilot program designed to teach CTSA hubs how to implement innovation and entrepreneurship programs at their home institutions.
Materials and methods
The program provided a 2-day onsite training experience combined with observation of an ongoing course focused on providing biomedical innovation, commercialization and entrepreneurial training to a medical academician audience (FFMI fastPACE).
All 9 participating CTSA institutes reported a greater connection to biomedical research commercialization resources. Six launched their own version of the FFMI fastPACE course or modified existing programs. Two reported greater collaboration with their technology transfer offices.
The FFMI fastPACE course and training program may be suitable for CTSA hubs looking to enhance innovation and entrepreneurship within their institutions and across their innovation ecosystems.
Polyaniline (PANI)/11% Multi-carbon nanotubes (MWCNT) nanocomposites sensors were synthesized through an in situ polymerization method. Frits compression method was adopted to make PANI/MWCNT. Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM) tests results showed that this technique produced a coating of PANI onto the MWCNT, which indicated that CNT were well dispersed in the polymer matrix. Several tests were run to evaluate the sensor's capabilities. The free end vibration test results showed that the double sided attachment of the sensor had higher damping ratio values than single sided attachment. Also, damping ratios were higher when the sensor was placed at the clamped end. Further, the strain sensing properties of PANI/MWCNT sensors were compared with the conventional foil strain gage. The dynamic sensing test results showed that over the range of 10–1000 Hz, the PANI/MWCNT composite sensor was consistently superior to the traditional foil strain gage for sensing purposes.
Higher fruit intake is associated with lower risk of all-cause and disease-specific mortality. However, data on individual fruits are limited, and the generalisability of these findings to the elderly remains uncertain. The objective of this study was to examine the association of apple intake with all-cause and disease-specific mortality over 15 years in a cohort of women aged over 70 years. Secondary analyses explored relationships of other fruits with mortality outcomes. Usual fruit intake was assessed in 1456 women using a FFQ. Incidence of all-cause and disease-specific mortality over 15 years was determined through the Western Australian Hospital Morbidity Data system. Cox regression was used to determine the hazard ratios (HR) for mortality. During 15 years of follow-up, 607 (41·7 %) women died from any cause. In the multivariable-adjusted analysis, the HR for all-cause mortality was 0·89 (95 % CI 0·81, 0·97) per sd (53 g/d) increase in apple intake, HR 0·80 (95 % CI 0·65, 0·98) for consumption of 5–100 g/d and HR 0·65 (95 % CI 0·48, 0·89) for consumption of >100 g/d (an apple a day), compared with apple intake of <5 g/d (Pfor trend=0·03). Our analysis also found that higher apple intake was associated with lower risk for cancer mortality, and that higher total fruit and banana intakes were associated lower risk of CVD mortality (P<0·05). Our results support the view that regular apple consumption may contribute to lower risk of mortality.
High blood pressure (BP) variability, which may be an important determinant of hypertensive end-organ damage, is emerging as an important predictor of cardiovascular health. Dietary antioxidants can influence BP, but their effects on variability are yet to be investigated. The aim of the present study was to assess the effects of vitamin E, vitamin C and polyphenols on the rate of daytime and night-time ambulatory BP variation. To assess these effects, two randomised, double-blind, placebo-controlled trials were performed. In the first trial (vitamin E), fifty-eight individuals with type 2 diabetes were given 500 mg/d of RRR-α-tocopherol, 500 mg/d of mixed tocopherols or placebo for 6 weeks. In the second trial (vitamin C–polyphenols), sixty-nine treated hypertensive individuals were given 500 mg/d of vitamin C, 1000 mg/d of grape-seed polyphenols, both vitamin C and polyphenols, or neither (placebo) for 6 weeks. At baseline and at the end of the 6-week intervention, 24 h ambulatory BP and rate of measurement-to-measurement BP variation were assessed. Compared with placebo, treatment with α-tocopherol, mixed tocopherols, vitamin C and polyphenols did not significantly alter the rate of daytime or night-time systolic BP, diastolic BP or pulse pressure variation (P>0·05). Treatment with the vitamin C and polyphenol combination resulted in higher BP variation: the rate of night-time systolic BP variation (P= 0·022) and pulse pressure variation (P= 0·0036) were higher and the rate of daytime systolic BP variation was higher (P= 0·056). Vitamin E, vitamin C or grape-seed polyphenols did not significantly alter the rate of BP variation. However, the increase in the rate of BP variation suggests that the combination of high doses of vitamin C and polyphenols could be detrimental to treated hypertensive individuals.
Since the drafting of Uganda's anti-homosexuality bill in 2009, considerable attention has been paid both in Uganda and across the African continent to the political and social significance of homosexual behaviour and identity. However, current debates have not adequately explained how and why anti-homosexual rhetoric has been able to gain such popular purchase within Uganda. In order to move beyond reductive representations of an innate African homophobia, we argue that it is necessary to recognise the deep imbrication of sexuality, family life, procreation and material exchange in Uganda, as well as the ways in which elite actors (including government officials, the media and religious leaders) are able to manipulate social anxieties to further particular ends. We employ a discourse analysis of reporting in the state-owned newspaper New Vision, first considering how the issue of homosexuality has been represented in relation to wider discourses regarding threats to public morality and national sovereignty. Then, through fieldwork undertaken in Uganda in 2009, we explore three key themes that offer deeper insights into the seeming resonance of this popular rhetoric about homosexuality: constructions of the family, the nature of societal morality, and understandings about reciprocity and material exchange in contemporary Ugandan society.