Activity

Rational drug design and in vitro pharmacology profiling constitute the gold standard in drug development pipelines. Problems arise, however, because this process is often difficult due to limited information regarding the complete identification of a molecule’s biological activities. The increasing affordability of genome-wide next-generation technologies now provides an excellent opportunity to understand a compound’s diverse effects on gene regulation. Here, we used an unbiased approach in lung and colon cancer cell lines to identify the early transcriptomic signatures of C-1305 cytotoxicity that highlight the novel pathways responsible for its biological activity. Our results demonstrate that C-1305 promotes direct microtubule stabilization as a part of its mechanism of action that leads to apoptosis. Furthermore, we show that C-1305 promotes G2 cell cycle arrest by modulating gene expression. The results indicate that C-1305 is the first microtubule stabilizing agent that also is a topoisomerase II inhibitor. This study provides a novel approach and methodology for delineating the antitumor mechanisms of other putative anticancer drug candidates.Food ingestion induces a metered response of the digestive system. Initially, the upper digestive system reacts to process and extract meal substrates. Later, meal residues not absorbed in the small bowel, pass into the colon and activate the metabolism of resident microbiota. DC661 in vitro Food consumption also induces sensations that arise before ingestion (e.g., anticipatory reward), during ingestion (e.g., gustation), and most importantly, after the meal (i.e., the postprandial experience). The postprandial experience involves homeostatic sensations (satiety, fullness) with a hedonic dimension (digestive well-being, mood). The factors that determine the postprandial experience are poorly understood, despite their potential role in personalized diets and healthy eating habits. Current data suggest that the characteristics of the meal (amount, palatability, composition), the activity of the digestive system (suited processing), and the receptivity of the eater (influenced by multiple conditioning factors) may be important in this context.This study analyzed the interrelationships between participation in MFRMs and dietary diversity of poultry farming households in Southeast Nigeria. We used cross-sectional data from poultry farmers in Southeast Nigeria and employed instrumental variable and seemingly unrelated regression models to estimate the impact of MFRM participation and major linkages to poultry farm households’ dietary diversity. The results show that participating in MFRMs, relative to traditional markets, improved poultry farmers’ dietary diversity. Moreover, dietary diversity was positively related to higher poultry farm incomes, higher value of own poultry products consumed, and larger area of vegetable cultivated using poultry droppings as manure. Furthermore, increased poultry farm income, higher value of own poultry products consumed, and larger area of vegetable land cultivated using poultry droppings as manure increased the dietary diversity of the farm households. In contrast, a higher share of poultry production revenue controlled by men reduced household dietary diversity. These findings make clear the potential of improving farming households’ nutrition outcomes by promoting participation in MFRMs and the major impact pathways.Professional education and public engagement are fundamental components of any antimicrobial stewardship (AMS) strategy. The National Institute for Health and Care Excellence (NICE), Public Health England (PHE), Health Education England (HEE) and other professional organisations, develop and publish resources to support AMS activity in primary care settings. The aim of this study was to explore the adoption and use of education/training and supporting AMS resources within NHS primary care in England. Questionnaires were sent to the medicines management teams of all 209 Clinical Commissioning Groups (CCGs) in England, in 2017. Primary care practitioners in 168/175 (96%) CCGs received AMS education in the last two years. Respondents in 184/186 (99%) CCGs reported actively promoting the TARGET Toolkit to their primary care practitioners; although 137/176 (78%) did not know what percentage of primary care practitioners used the TARGET toolkit. All respondents were aware of Antibiotic Guardian and 132/167 (79%) reported promoting the campaign. Promotion of AMS resources to general practices is currently excellent, but as evaluation of uptake or effect is poor, this should be encouraged by resource providers and through quality improvement programmes. Trainers should be encouraged to promote and highlight the importance of action planning within their AMS training. AMS resources, such as leaflets and education, should be promoted across the whole health economy, including Out of Hours and care homes. Primary care practitioners should continue to be encouraged to display a signed Antibiotic Guardian poster as well as general AMS posters and videos in practice, as patients find them useful and noticeable.Robertsonian translocations are common chromosomal alterations. Chromosome variability affects human health and natural evolution. Despite the significance of such mutations, no mechanisms explaining the emergence of such translocations have yet been demonstrated. Several models have explored possible changes in interphase nuclei. Evidence for non-homologous chromosomes end joining in meiosis is scarce, and is often limited to uncovering mechanisms in damaged cells only. This study presents a primarily qualitative analysis of contacts of non-homologous chromosomes by short arms, during meiotic prophase I in the mole vole, Ellobius alaicus, a species with a variable karyotype, due to Robertsonian translocations. Immunocytochemical staining of spermatocytes demonstrated the presence of four contact types for non-homologous chromosomes in meiotic prophase I (1) proximity, (2) touching, (3) anchoring/tethering, and (4) fusion. Our results suggest distinct mechanisms for chromosomal interactions in meiosis. Thus, we propose to change the translocation mechanism model from ‘contact first’ to ‘contact first in meiosis’.