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71.
In this essay, we present three case studies which suggest that sometimes we are better off supporting a so–called irrational suicide, and that emotional or psychological distress – even if medically controllable – might justify a suicide. We underscore how complicated these decisions are and how murky a physician's moral role can be. We advocate a more individualized route to end–of–life care, eschewing well–meaning, principled, generalizations in favor of a highly contextualized, patient–centered, approach. We conclude that our Western traditions of promoting reasoned behavior and life themselves may at times be counter–productive. 相似文献
72.
Leahy JJ Golding BT Griffin RJ Hardcastle IR Richardson C Rigoreau L Smith GC 《Bioorganic & medicinal chemistry letters》2004,14(24):6083-6087
A solution-phase multiple-parallel synthesis approach was employed for the preparation of 6-, 7- and 8-aryl-substituted chromenone libraries, which were screened as inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). These studies resulted in the identification of 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) as a highly potent and selective DNA-PK inhibitor (IC50 = 14 nM), exhibiting ATP-competitive inhibition kinetics. 相似文献
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Petra Liskova Lubica Dudakova Cerys J. Evans Karla E. Rojas Lopez Nikolas Pontikos Dimitra Athanasiou Hodan Jama Josef Sach Pavlina Skalicka Viktor Stranecky Stanislav Kmoch Caroline Thaung Martin Filipec Michael E. Cheetham Alice E. Davidson Stephen J. Tuft Alison J. Hardcastle 《American journal of human genetics》2018,102(3):447-459
75.
Yeast forms of the dimorphic fungus Cladosporium werneckii grow by polar budding and yield a homogeneous yeast phase when cultured at 21 C in an agitated sucrose-salts medium (Czapek-Dox broth). Yeast extract enrichment of such a yeast phase consisting of 104 yeasts per ml induces a quantitative conversion of the yeasts to true hyphae. This conversion is not mediated by a transition cell and is often attended by capsule formation. When 105 or 106 yeasts per ml receive enrichment, a nonquantitative conversion to moniliform hyphae is effected and no capsule formation is observed. Rapid agitation compared to slow agitation or stationary incubation of the nutritionally mediated conversion cultures greatly accelerates the production of lateral hyphal buds or their yeast progenies. These cells appear incapable of undergoing nutritional conversion to hyphae, but instead must grow for several generations in the unenriched sucrose-salts medium to restore conversion competence. Temperature shifts affect directly the morphology and morphogenesis of the yeast in unenriched medium; at 17 C yeasts are smaller and more ovoid than at 21 C, and at 30 C marked conversion of yeasts to moniliform hyphae occurs. A methodology employing the Coulter counter and Coulter channelizer provides evidence that direct correlations do not always exist between the optimum conditions for the growth of C. werneckii and the optimum conditions for its yeast-to-mold conversion. 相似文献
76.
Danniel Thiago Fraz?o Luiz Fernando de Farias Junior Teresa Cristina Batista Dantas Kleverton Krinski Hassan Mohamed Elsangedy Jonato Prestes Sarah J. Hardcastle Eduardo Caldas Costa 《PloS one》2016,11(3)
ObjectivesTo examine the affective responses during a single bout of a low-volume HIIE in active and insufficiently active men.ResultsThere were similar positive affective responses to the first three work bouts between insufficiently active and active men (p > 0.05). However, insufficiently active group displayed lower affective responses over time (work bout 4 to 10) than the active group (p < 0.01). Also, the insufficiently active group displayed lower values of mean, lowest, and highest affective response, as well as lower values of affective response at the highest RPE than the active group (p < 0.001). There were no differences in the RPE and HR between the groups (p > 0.05).ConclusionsInsufficiently active and active men report feelings of pleasure to few work bouts (i.e., 3–4) during low-volume HIIE, while the affective responses become more unpleasant over time for insufficiently active subjects. Investigations on the effects of low-volume HIIE protocols including a fewer number of work bouts on health status and fitness of less active subjects would be interesting, especially in the first training weeks. 相似文献
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Alice?E. Davidson Nele Schwarz Lina Zelinger Gabriele Stern-Schneider Amelia Shoemark Benjamin Spitzbarth Menachem Gross Uri Laxer Jacob Sosna Panagiotis?I. Sergouniotis Naushin?H. Waseem Robert Wilson Richard?A. Kahn Vincent Plagnol Uwe Wolfrum Eyal Banin Alison?J. Hardcastle Michael?E. Cheetham Dror Sharon Andrew?R. Webster 《American journal of human genetics》2013,93(2):321-329
Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101−1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function. 相似文献
80.
Structure of the Ire1 autophosphorylation complex and implications for the unfolded protein response 总被引:1,自引:0,他引:1