N-Phenyl-4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R phosphoinositide-3-kinase (PI3Kα)

This work describes our efforts to optimize the lead PI3Kα inhibitor N-benzyl 4-hydroxy-2-quinolone-3-carboxamide using structure-based design and molecular docking. We identified a series of N-phenyl 4-hydroxy-2-quinolone-3-carboxamides as selective inhibitors of mutant H1047R versus wild-type PI3Kα and we also showed that the cell growth inhibition by these compounds likely occurs by inhibiting the formation of pAKT and induction of apoptosis.     

The importance of species range attributes and reserve configuration for the conservation of angiosperm diversity in Western Australia

In order to better understand the relationship between reserve design and the species represented by such designs, we examined the effectiveness of the Western Australian reserve system for conserving angiosperm diversity, and examined the characteristics of those species conserved. We overlayed species distribution data for 14 plant lineages with the distribution of the reserve system (8.5% of the State’s area) and identified the species that remained unprotected. We found that, depending upon the method employed, between 174 (5.7%) and 570 (18.7%) of species were not included within the reserve system. Two main unprotected regions were identified, one of which was also a centre of high diversity. Geographical range sizes of unprotected species were six times smaller than those species that were protected, while species richness of small-ranged endemic species coincided with general patterns of species richness. At the level of Western Australia’s bioregions we found that conservation effectiveness was most dependent on characteristics of the reserve system rather than characteristics (size and positioning) of species ranges. At this scale, the most effective way to conserve more species in Western Australia would be to conserve more land, while conservation would be most successful in a uniformly dispersed reserve system. Our results highlight the fact that reserve systems may take on two design approaches based on scale––at continental scales, reserves should be clustered around the hotspots of endemic species, while within regions, an evenly distributed reserve system will most adequately sample species.     

The three-dimensional macronutrient niche of an invasive generalist predator

1. Harvestmen are predators, although they suspected of being partly omnivorous by including fruits in their diet. 2. In the present study, the right-angled mixture triangle (RMT) was used to analyse the macronutritional niche of the harvestman Opilio canestrinii, an invasive species in northern Europe. The study design followed a double-test procedure in which the animals were subjected to two self-selection tests: the first one immediately after being caught in the field and the second after 1 week of ad libitum feeding during which the animals became satiated and nutritionally balanced. A comparison of results from the two tests indicates whether the animals were food limited in the field, and whether they were limited by a particular macronutrient. 3. Females were found to be food limited in the field, whereas males were not. Opilio canestrinii had a target intake of 28% lipid : 52% protein : 20% carbohydrate [i.e. with a considerable proportion of carbohydrate (sugar) in the diet]. Both sexes were non-protein limited in the field, with sugar being more limiting than lipid. 4. The results indicate considerable inclusion of plant-derived sugar in the natural diet. This conclusion was supported by a separate experiment showing enhanced performance (survival, gain in mass) in animals whose only energy supply was fresh fruit. 5. It is concluded that the harvestman is best characterized as an omnivorous predator.     

Expression and sequence analysis of a Treponema pallidum gene, tpn38(b), encoding an exported protein with homology to T. pallidum and Borrelia burgdorferi proteins

Abstract An Escherichia coli clone containing recombinant plasmid C19 was identified from a Treponema pallidum genomic DNA library by in situ immunoassay. E. coli maxicells containing pC19 synthesized a treponemal protein doublet of 39.2 and 38.2 kDa, designated TpN38(b). Pulse-chase and protein processing studies showed that TpN38(b) is synthesized with a cleavable amino-terminal signal peptide. A 2.0-kb fragment of pC19 containing the tpn38(b) gene was subcloned and sequenced. The tpn38(b) gene is 1029 nucleotides long and encodes a protein of 343 amino acids with a calculated molecular mass of 37.9 kDa. The deduced amino acid sequence of TpN38(b) has homology with the T. pallidum TpN35 lipoprotein and the Borrelia burgdorferi BmpA, BmpB, BmpC, and BmpD proteins.     

Structure and transcription of genes within the β-hbd-adh1 region of Clostridium acetobutylicum P262

Abstract The 1.2-kb DNA fragment upstream of the linked β- hbd (3-hydroxybutyryl-CoA dehydrogenase) and adh1 (NADPH-dependent alcohol dehydrogenase) genes from Clostridium acetobutylicum P262 was sequenced. The upstream region contained an open reading frame (ORFB) which was found to have 44% amino acid identity to the fixB gene products of yRhizobium and Azorhizobium . The β- hbd and ORFB genes were expressed during the acidogenic and solventogenic phases. The β- hbd gene was transcribed on a single mRNA species of 2.0 kb, whereas the ORFB gene was transcribed on two species of mRNA of 2.0 and 3.5 kb, respectively. The adh1 gene was induced or derepressed at the pH breakpoint before the onset of solventogenesis and was transcribed on a single species of mRNA of 2.4 kb.     

Metasynthesis of Youth Suicidal Behaviours: Perspectives of Youth,Parents, and Health Care Professionals

BackgroundYouth suicide is a major public health issue throughout the world. Numerous theoretical models have been proposed to improve our understanding of suicidal behaviours, but medical science has struggled to integrate all the complex aspects of this question. The aim of this review is to synthesise the views of suicidal adolescents and young adults, their parents, and their healthcare professionals on the topics of suicidal behaviour and management of those who have attempted suicide, in order to propose new pathways of care, closer to the issues and expectations of each group.ConclusionThe violence of the message of a suicidal act and the fears associated with death lead to incomprehension and interfere with the capacity for empathy of both family members and professionals. The issue in treatment is to be able to witness this violence so that the patient feels understood and heard, and thus to limit recurrences.     

The Body Mass Index-Mortality Link across the Life Course: Two Selection Biases and Their Effects

In this study, we investigated two selection biases that may affect the obesity-mortality link over the life course: mortality selection and healthy participant effects. If these selection mechanisms are stronger among obese adults than among non-obese adults, they may contribute to the weakening obesity-mortality link over the life course. We used data from the National Health and Nutrition Examination Survey 1988–2010 with linked mortality files from 1988–2011. We employed weighted Cox models to test and adjust for these two selection biases. We also used complementary log-log models, adjusted for a normal distribution of frailty, to test for mortality selection effects; accelerated failure-time models to mitigate the mortality selection effect; and ordinary least squares regression to test for healthy participant effects. The link between class II/III obesity and mortality weakens at older ages. We did not find evidence for significant mortality selection or healthy participant effects. Also, even if the healthy participant effects were stronger among obese adults, they are not strong enough to produce a weakening association between obesity and morbidity at higher ages at the time of the survey. Therefore, neither of these selection biases explains the diminishing effect of class II/III obesity on mortality over the life course.