Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging ...payloads represented by the flagship of this family of antitumor agents,
-acetyl calicheamicin Formula: see text, have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.
Stress granule formation is triggered by the release of mRNAs from polysomes and is promoted by the action of the RNA-binding proteins G3BP1/2. Stress granules have been implicated in several disease ...states, including cancer and neurodegeneration. Consequently, compounds that limit stress granule formation or promote their dissolution have potential as both experimental tools and novel therapeutics. Herein, we describe two small molecules, G3BP inhibitor a and b (G3Ia and G3Ib), designed to bind to a specific pocket in G3BP1/2 that is targeted by viral inhibitors of G3BP1/2 function. In addition to disrupting the co-condensation of RNA, G3BP1, and caprin 1 in vitro, these compounds inhibit stress granule formation in cells treated prior to or concurrent with stress and dissolve pre-existing stress granules. These effects are consistent across multiple cell types and a variety of initiating stressors. Thus, these compounds represent powerful tools to probe the biology of stress granules and hold promise for therapeutic interventions designed to modulate stress granule formation.
Despite consensus that exposure to media images of thin fashion models is associated with poor body image and disordered eating behaviours, few attempts have been made to enact change in the media. ...This study sought to investigate an effective alternative to current media imagery, by exploring the advertising effectiveness of average-size female fashion models, and their impact on the body image of both women and men. A sample of 171 women and 120 men were assigned to one of three advertisement conditions: no models, thin models and average-size models. Women and men rated average-size models as equally effective in advertisements as thin and no models. For women with average and high levels of internalisation of cultural beauty ideals, exposure to average-size female models was associated with a significantly more positive body image state in comparison to exposure to thin models and no models. For men reporting high levels of internalisation, exposure to average-size models was also associated with a more positive body image state in comparison to viewing thin models. These findings suggest that average-size female models can promote positive body image and appeal to consumers.
Indoor environmental health is now recognized as an important factor in preventing respiratory health problems in the United States. It is also a concern in Canada due to the amount of time that ...Canadians spend indoors because of cold weather and the potential for increased time indoors during the summer if the climate warms. The negative health effects are often labeled as sick building syndrome, but diagnosing a building or its occupants as sick is complicated by the variety of symptoms, the presence of chronic versus acute symptoms and social and psychological (socio-psychological) factors that may reduce the effectiveness of an engineering solution. As a case study, the contribution of various factors to indoor environmental health, in three buildings at the University of Toronto, was examined using five different methods. The results indicate that the inhabitants of the buildings consider features other than air quality in considering building health such as design, maintenance, funding cuts and socio-psychological factors.
This article used data from 5,171 young women participating in the Australian Longitudinal Study on Women's Health, a nationally representative longitudinal cohort study, to identify longitudinal ...trajectory patterns of mental health across 6 surveys over 16 years of early adulthood, from age 18-23 to age 34-39. In addition, we identified both predictors and outcomes of these trajectories. Using group-based trajectory modeling, we identified 4 distinct trajectory groups of mental health. The mental health of most participants (55%) was consistently high, with 12% improving, 24% varying, and 9% frequently low. The authors considered characteristics at the beginning and end of the trajectory period, taking a life-course perspective to understand vulnerabilities to, and outcomes of, low or variable poor mental health trajectories. Financial difficulties, poor general health, and weight or shape dissatisfaction were characteristics at Survey 1 that distinguished all other trajectory groups from those with consistently high mental health. Other differences were specific to 1 or 2 groups. By the end of the trajectory period, the improving mental health group showed few differences from those with consistently high mental health. However, those with varying and low mental health showed evidence of social disadvantage, poor physical and emotional health, and unhealthy behaviors, and were less likely to be mothers. The ability to identify distinct trajectories of mental health in early adulthood, and their correlates, provides evidence to underpin population health interventions targeting the prevention of mental health problems among this population group.
Current neural prostheses use electricity as the mode of stimulation, yet information transfer in neural circuitry is primarily through chemical transmitters. To address this disparity, this study ...was conducted to devise a prototype interface for a retinal prosthetic based on localized chemical delivery. The goal was to determine whether fluidic delivery through microfabricated apertures could be used to stimulate at single-cell dimensions.
A drug delivery system was microfabricated based on a 5- or 10- microm aperture in a 500-nm thick silicon nitride membrane to localize and limit transmitter release. The aperture overlies a microfluidic delivery channel in a silicone elastomer. To demonstrate the effectiveness of this transmitter-based prosthesis, rat pheochromocytoma cells (PC12 cell line) were grown on the surface of the device to test the precision of stimulation, using bradykinin as a stimulant and measuring fluorescence from the calcium indicator, fluo-4.
The extent of stimulation could be controlled accurately by varying the concentration of stimulant, from a single cell adjacent to the aperture to a broad area of cells. The stimulation radius was as small as 10 microm, corresponding to stimulation volumes as small as 2 pL. The relationship between the extent of stimulation and concentration was linear.
The demonstration of localized chemical stimulation of excitable cells illustrates the potential of this technology for retinal prostheses. Although this is only a proof of concept of neurotransmitter stimulation for a retinal prosthesis, it is a significant first step toward mimicking neurotransmitter release during synaptic transmission.
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