Synthetic Approaches to Complex Naturally Occurring Coumarins

Synthetic routes to the naturally occurring coumarins glabralactone and the more complex dentatin have been developed to provide unequivocal proof of their structures. The structure assigned to angelicone, an isomer of glabralactone, has also been synthesised, by an unambiguous pathway. As a consequence of this work, the published structure of angelicone has been shown to be incorrect. A key step in each of these syntheses has been the base-catalysed retro-Michael opening of a chrom-anone ring, to generate a phenolic coumarin containing an ortho senecioyl grouping. Additionally, base treatment in this manner has provided, by coumarin ring opening and alternative reclosure, a method for the efficient synthesis of both 6- and 8-senecioyl-5,7-dioxygenated coumarins. The above described chromanone ring opening and coumarin ring Isomerisation processes have also been utilised in the synthesis of dentatin, a linear chromenocoumarin whose structure had been based on spectroscopic data only. The 1,1-dimethylallyl group at C-8 was introduced by the ortho-Claisen rearrangement of the 7-O-(3,3-dimethylallyl) ether derived from a readily available phenolic chromanocoumarin. The further rearrangements to which this type of alkenyl is prone, were deliberately prevented by having a senecioyl group at C-6. The rapid intramolecular cyclisation of this group with the 7-hydroxyl liberated during the Claisen rearrangement, resulted, in high yield, in the formation of a linear chromanocoumarin having the correct carbon skeleton and oxygenation pattern of the natural product. Further careful reduction and dehydration proceeded smoothly to give pure dentatin. Preliminary investigations have been directed towards the syntheses of some structurally complex natural 4-alkyl coumarins which have recently been shown to possess important physiological activity. The reaction of 2,2-dimethy1-5,7-dihydroxychroman-4-one with acetylene dicarboxylic acid dimethyl ester has given two new isomeric 4-carbomethoxy chromanocoumarins The structures of these have been assigned on both spectroscopic and chemical evidence. Attempts to modify the carbomethoxy group and to induce chromanone ring opening have been made. The corresponding 4-methyl analogues have been prepared and shown to be resistant to oxidation

Patient decision-making about emergency and planned stoma surgery for IBD: a qualitative exploration of patient and clinician perspectives

Background: Many IBD patients worry about stoma forming surgery (SFS), sometimes enduring poor bowel-related quality of life to avoid it. Anticipation of SFS and whether expectations match experience is under-reported. This qualitative study explored influences on patients’ SFS decision-making, and compared pre-operative concerns with post-operative outcomes. Methods: We purposively recruited participants with IBD from UK hospital outpatient and community sources, and IBD clinicians from public hospitals. Four focus groups and 29 semi-structured patient participant interviews, and 18 clinician interviews were audio recorded, transcribed, and analysed thematically. Participants had a current temporary, recently-reversed, or permanent stoma, or were stoma naïve. Results: Four themes emerged: Pre-operative concerns and expectations, Patient decision-making, Surgery and recovery, and Long-term outcomes. Participants and clinicians agreed about most pre-operative concerns, that outcomes were often better than expected, and support from others with a stoma is beneficial. Patient decision-making involves multiple factors, including disease status. Some clinicians avoid discussing SFS, and the phrase ‘last resort’ can bias patient perceptions; others recommend early discussion, increasing dialogue when medical management becomes ineffective. The post-operative period is particularly challenging for patients. Stoma acceptance is influenced by personal perceptions and pre- and post-operative clinical and social support. Conclusion: Patients need balanced information on all treatment options, including surgery, from an early stage. Early multi-disciplinary team dialogue about SFS, and contact with others living well with a stoma, could enable informed decision-making. Life with a stoma is often better than anticipated, improving quality of life and control. Ongoing specialist nursing support aids recovery and adjustment

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

Narrative ethics in postcolonial fiction

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Predicting Grizzly Bear Density in Western North America

Conservation of grizzly bears (Ursus arctos) is often controversial and the disagreement often is focused on the estimates of density used to calculate allowable kill. Many recent estimates of grizzly bear density are now available but field-based estimates will never be available for more than a small portion of hunted populations. Current methods of predicting density in areas of management interest are subjective and untested. Objective methods have been proposed, but these statistical models are so dependent on results from individual study areas that the models do not generalize well. We built regression models to relate grizzly bear density to ultimate measures of ecosystem productivity and mortality for interior and coastal ecosystems in North America. We used 90 measures of grizzly bear density in interior ecosystems, of which 14 were currently known to be unoccupied by grizzly bears. In coastal areas, we used 17 measures of density including 2 unoccupied areas. Our best model for coastal areas included a negative relationship with tree cover and positive relationships with the proportion of salmon in the diet and topographic ruggedness, which was correlated with precipitation. Our best interior model included 3 variables that indexed terrestrial productivity, 1 describing vegetation cover, 2 indices of human use of the landscape and, an index of topographic ruggedness. We used our models to predict current population sizes across Canada and present these as alternatives to current population estimates. Our models predict fewer grizzly bears in British Columbia but more bears in Canada than in the latest status review. These predictions can be used to assess population status, set limits for total human-caused mortality, and for conservation planning, but because our predictions are static, they cannot be used to assess population trend

Combining stable isotope ratios with elemental concentrations to improve the estimation of terrestrial carnivore diets

Stable isotopes of animal tissue have been used to estimate diet for many consumer species and places, but the ability to assign contributions to all food items is limited by the number of tracers used, and the separation of the tracer data among the dietary sources. We tested whether we could detect caribou (Rangifer tarandus) in the diet of individual predators in southwest Canada, where caribou are endangered. The separation between caribou tissue and that of other common prey was minimal using C13 and N15 isotope ratios and our confidence in assigning the caribou diet fraction correctly was low despite testing several fractionation values and priors. We measured the concentration of a suite of elements in the tissue of lichen, large prey and predators to investigate whether we could use an elemental concentration as a diet tracer and better assign the caribou diet fraction, because several of these elements were known to be more abundant in lichen, a major food for caribou in winter. Strontium and cesium had higher concentrations, when normalized by a common salt (we chose calcium), in caribou tissue than the other prey species we measured; this was also true for strontium isotope ratios. The elemental tracers appeared to overestimate caribou in the diet however, we suggest that the addition of either cation could yield finer and more accurate estimates of diet for large terrestrial predators after further investigation. The addition of a strontium isotope ratio tracer to a diet investigation may be equally informative and require less pre-work, because one ratio (Sr87/Sr86) has already been well studied

Observed versus predicted values of grizzly bear density (bears/1000 km²) using the best fit interior model described in Table 4.

<p>Data included 76 inventoried study areas and 14 unoccupied areas across the interior of western North America. Error bars are 95% confidence limits for observed data derived from the survey results or estimated subjectively, based on survey methods (see Methods for detailed description). The cases with the largest residuals often had the greatest error and were hence weighted lower in the regression.</p

A summary of predicted numbers of grizzly bears in Canada and in National Parks by province, based on the coastal and interior models developed in this paper.

<p>–5 WMUs), and territorial guide territory boundaries which were roughly similar to WMUs in size. We predicted density for small portions of each province using ecological unit mapping (ecoregions-the largest units used), provincial wildlife management units (WMUs), provincial grizzly bear population units (GBPUs, groups of 1</p><p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082757#pone.0082757-FestaBianchet1" target="_blank">[94]</a> with corrections for portions of the National Parks that were not included.^a</p>b<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082757#pone.0082757-Hamilton2" target="_blank">[92]</a>.</p>c<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082757#pone.0082757-McLoughlin1" target="_blank">[9]</a>.</p

Estimates of grizzly bear density in North America.

<p>Areas currently unoccupied are filled with hatching. The presence of black bears throughout the study area is denoted by a black outline, partial presence of black bears by a gray outline and a hatched gray or no outline means black bears did not occur on the study area. Areas without salmon are not colour filled, those with abundant salmon are filled in red, and those where salmon were present but not abundant in rose. The black bear distribution in North America is shown in tan <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082757#pone.0082757-Laliberte1" target="_blank">[91]</a>.</p