CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery ...of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
Adipose tissue (AT) is distributed as large differentiated masses, and smaller depots covering vessels, and organs, as well as interspersed within them. The differences between types and size of ...cells makes AT one of the most disperse and complex organs. Lipid storage is partly shared by other tissues such as muscle and liver. We intended to obtain an approximate estimation of the size of lipid reserves stored outside the main fat depots. Both male and female rats were made overweight by 4-weeks feeding of a cafeteria diet. Total lipid content was analyzed in brain, liver, gastrocnemius muscle, four white AT sites: subcutaneous, perigonadal, retroperitoneal and mesenteric, two brown AT sites (interscapular and perirenal) and in a pool of the rest of organs and tissues (after discarding gut contents). Organ lipid content was estimated and tabulated for each individual rat. Food intake was measured daily. There was a surprisingly high proportion of lipid not accounted for by the main macroscopic AT sites, even when brain, liver and BAT main sites were discounted. Muscle contained about 8% of body lipids, liver 1-1.4%, four white AT sites lipid 28-63% of body lipid, and the rest of the body (including muscle) 38-44%. There was a good correlation between AT lipid and body lipid, but lipid in "other organs" was highly correlated too with body lipid. Brain lipid was not. Irrespective of dietary intake, accumulation of body fat was uniform both for the main lipid storage and handling organs: large masses of AT (but also liver, muscle), as well as in the "rest" of tissues. These storage sites, in specialized (adipose) or not-specialized (liver, muscle) tissues reacted in parallel against a hyperlipidic diet challenge. We postulate that body lipid stores are handled and regulated coordinately, with a more centralized and overall mechanisms than usually assumed.
When the invention of photography was publicly announced in 1839, the new medium was soon perceived as an essential tool for surveying new territories. From the early 1850s the Government of India ...made official the recording of architecture and antiquities and sponsored several photographic expeditions. This article presents the development of official photography in India from its inception in the mid-1850s to the late 1860s, focusing primarily on the work of two important practitioners, Linnaeus Tripe and Edmund David Lyon, who were both employed by the Government of Madras. Separated by ten years, Tripe and Lyon travelled throughout South India during their employment with the Madras Presidency and frequently recorded the same sites. A comparison of their work reveals the changes that arose in the concept of delineating architecture and antiquities between the 1850s and the 1860s and the alterations which the recorded monuments underwent in that time, as well as enabling the compositional styles adopted by both practitioners to be studied for the first time.
Indigenous people in North America and around the world are in dire circumstances with respect to language maintenance and cultural continuation. However, Indigenous communities are also taking back ...increasing control of the education of their children. In so doing, they are frequently exploring culture-based education and language immersion models as a means of perpetuating language by passing it on to the youngest generation. This is the goal of the Mnidoo Mnising Anishinabek Kinoomaage Gaming (MMAK) Anishinaabemowin (Ojibwe) immersion school on Manitoulin Island. In this paper, we describe the linguistic results of early years education at the MMAK. We begin with a description of the development of the MMAK and share its successes and challenges in the framework of larger policy developments in the region. We then discuss the linguistic outcomes thus far for students in the MMAK; having collected data with Junior and Senior Kindergarten students over the past two years using multiple assessment methods, we have been able to establish clear patterns with respect to the impact of Anishinaabemowin language immersion on the language development of these students. Finally, we explore how Aboriginal language immersion may be a tool for language revitalization for this and other communities.
Temporal preparation was assessed in 15 Alzheimer’s disease (AD) patients, 20 persons with mild cognitive impairment (MCI) and 28 healthy older adults. Participants completed a simple reaction time ...task in which the preparatory interval duration varied randomly within two blocks (short versus long temporal window). Results indicated that AD and MCI patients had difficulty preparing for the shortest preparatory interval of the short temporal window. AD and MCI patients also had difficulty maintaining an optimal level of preparation up to 5 s within the short temporal window. These results suggest that AD and MCI patients might show difficulty preparing for rapidly occurring events and maintaining preparation over time. This phenomenon should be considered when using reaction time measures with such patients.
The British Columbia Farmers’ Market Nutrition Coupon Program (BC FMNCP) provides households with low incomes with coupons to purchase healthy foods from farmers’ markets.
To examine the impact of ...the BC FMNCP on the short-term household food insecurity, malnutrition risk, mental well-being, sense of community (secondary outcomes), and subjective social status (exploratory outcome) of adults with low incomes post-intervention and 16 weeks post-intervention.
Secondary analyses from a pragmatic randomized controlled trial conducted in 2019 that collected data at baseline, post-intervention, and 16 weeks post-intervention.
Adults ≥18 years with low incomes were randomized to an FMNCP group (n = 143) or a no-intervention control group (n = 142).
Participants in the FMNCP group received 16 coupon sheets valued at $21 Canadian dollars (CAD)/sheet over 10 to 15 weeks to purchase healthy foods from farmers’ markets and were eligible to participate in nutrition skill-building activities.
Outcomes included short-term household food insecurity (modified version of Health Canada’s 18-item Household Food Security Survey Module), malnutrition risk (Malnutrition Universal Screening Tool), mental well-being (Warwick-Edinburgh Mental Well-Being Scale), sense of community (Brief Sense of Community Scale), and subjective social status (MacArthur Scale of Subjective Social Status community scale).
Mixed-effects linear regression and multinomial logistic regression examined between-group differences in outcomes post-intervention and 16 weeks post-intervention.
The risk of marginal and severe short-term household food insecurity was lower among those in the FMNCP group compared with those in the control group (relative risk ratio RRR 0.15, P = 0.01 and RRR 0.16, P = 0.02) post-intervention, with sustained reductions in severe household food insecurity 16 weeks post-intervention (RRR 0.11, P = 0.01). No statistically significant differences were observed in malnutrition risk, mental well-being, sense of community, or subjective social status post-intervention or 16 weeks post-intervention.
The BC FMNCP reduced short-term household food insecurity but was not found to improve malnutrition risk or psychosocial well-being among adults with low incomes compared with a no-intervention control group.
Among T3 receptors, TRα1 is ubiquitous and its deletion or a specific expression of a dominant-negative TRα1 isoform in Sertoli cell leads to an increase in testis weight and sperm production. The ...identification of a 43-kDa truncated form of the nuclear receptor TRα1 (p43) in the mitochondrial matrix led us to test the hypothesis that this mitochondrial transcription factor could regulate Sertoli cell proliferation. Here we report that p43 depletion in mice increases testis weight and sperm reserve. In addition, we found that p43 deletion increases Sertoli cell proliferation in postnatal testis at 3 days of development. Electron microscopy studies evidence an alteration of mitochondrial morphology observed specifically in Sertoli cells of p43-/- mice. Moreover, gene expression studies indicate that the lack of p43 in testis induced an alteration of the mitochondrial-nuclear cross-talk. In particular, the up-regulation of Cdk4 and c-myc pathway in p43-/- probably explain the extended proliferation recorded in Sertoli cells of these mice. Our finding suggests that T3 limits post-natal Sertoli cell proliferation mainly through its mitochondrial T3 receptor p43.
Adults with low incomes have lower diet quality than their higher income counterparts. In Canada, the British Columbia Farmers’ Market Nutrition Coupon Program (FMNCP) provides coupons to low-income ...households to purchase healthy foods in farmers’ markets.
The objective of this study was to examine the impact of the FMNCP on the diet quality of adults with low incomes.
In a pragmatic randomized controlled trial conducted in 2019, adults with low incomes (≥18 y) were randomly assigned either to an FMNCP intervention (n = 143) or a no-intervention control group (n = 142). The FMNCP group received 16 coupon sheets valued at $21 per sheet over 10–15 wk to purchase healthy foods from farmers’ markets. Participants completed a questionnaire and 2 24-h dietary recalls at baseline (0 wk), immediately post-intervention (10–15 wk), and 16-wk post-intervention (26–31 wk). Diet quality was calculated using the Healthy Eating Index-2015 (HEI-2015). Linear mixed-effects regression assessed differences in HEI-2015 total (primary outcome) and component scores (secondary outcomes) between the FMNCP and control groups at post-intervention and 16-wk post-intervention. Subgroup analyses examined program impacts by sex and age group (18–59 y, ≥60 y).
There were no significant differences in HEI-2015 total scores between the FMNCP and control groups at post-intervention (−0.07; 95% CI: −4.07, 3.93) or 16-wk post-intervention (1.22; 95% CI: −3.00, 5.44) overall or between subgroups. There were no significant between-group differences in HEI-2015 component scores at post-intervention, although there were significant differences in component scores for dairy and fatty acids at 16-wk post-intervention.
The FMNCP did not significantly improve diet quality among adults with low incomes over the study period. Further research is needed to explore whether higher subsidy amounts or a longer intervention period is needed to meaningfully improve diet quality among adults with low incomes.
This trial was registered at clinicaltrials.gov as NCT03952338.
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