‘It’s Always About the Eating Disorder’: Finding the Person Through Recovery-Oriented Practice for Bulimia

Culture, Medicine, and Psychiatry - Bulimia is an eating disorder characterised primarily by binging and ‘inappropriate’ compensatory behaviours, such as purging or excessive exercise....     

Plasticity in flower size as an adaptation to variation in pollinator specificity

1. Mutualisms, including plant-pollinator interactions, are an important component of ecosystems. 2. Plants can avoid the costs of variation in pollinator benefit by maintaining specificity. 3. We hypothesise a novel mechanism to ensure specificity, which takes advantage of the cognitive abilities of specific pollinators to exclude non-specific flower visitors. 4. Inflorescences of the tropical vine genus Psiguria produce flowers at regular intervals, with subsequent flowers smaller than predecessors. 5. The principle pollinators, Heliconius spp., possess an excellent spatial memory. 6. Therefore, decreasing flower size may ensure specific pollination: once Heliconius individuals have learnt the location of an inflorescence they will return, but inconspicuous flowers should reduce visits by non-specific pollinators with poorer spatial memories. 7. We tested the predictions of this hypothesis with field experiments in Panama. We confirmed that flowers on inflorescences are smaller than their predecessors. 8. Paired experiments showed that larger flowers attracted more pollinators and that the presence of an initial large flower increased subsequent visitation by Heliconius spp. to small flowers, indicating learning behaviour. 9. These results suggest that learning behaviour and decreasing flower size maintain visits from specific pollinators while reducing those from non-specific pollinators. We propose this as a novel mechanism for promoting pollinator specificity and discuss its ecological significance.     

Cumulative deamidations of the major lens protein γS‐crystallin increase its aggregation during unfolding and oxidation

Age‐related lens cataract is the major cause of blindness worldwide. The mechanisms whereby crystallins, the predominant lens proteins, assemble into large aggregates that scatter light within the lens, and cause cataract, are poorly understood. Due to the lack of protein turnover in the lens, crystallins are long‐lived. A major crystallin, γS, is heavily modified by deamidation, in particular at surface‐exposed N14, N76, and N143 to introduce negative charges. In this present study, deamidated γS was mimicked by mutation with aspartate at these sites and the effect on biophysical properties of γS was assessed via dynamic light scattering, chemical and thermal denaturation, hydrogen‐deuterium exchange, and susceptibility to disulfide cross‐linking. Compared with wild type γS, a small population of each deamidated mutant aggregated rapidly into large, light‐scattering species that contributed significantly to the total scattering. Under partially denaturing conditions in guanidine hydrochloride or elevated temperature, deamidation led to more rapid unfolding and aggregation and increased susceptibility to oxidation. The triple mutant was further destabilized, suggesting that the effects of deamidation were cumulative. Molecular dynamics simulations predicted that deamidation augments the conformational dynamics of γS. We suggest that these perturbations disrupt the native disulfide arrangement of γS and promote the formation of disulfide‐linked aggregates. The lens‐specific chaperone αA‐crystallin was poor at preventing the aggregation of the triple mutant. It is concluded that surface deamidations cause minimal structural disruption individually, but cumulatively they progressively destabilize γS‐crystallin leading to unfolding and aggregation, as occurs in aged and cataractous lenses.     

Fetal uninephrectomy in male sheep alters the systemic and renal responses to angiotensin II infusion and AT1R blockade

Fetal uninephrectomy (uni-x) at 100 days of gestation results in compensatory nephrogenesis in the remaining kidney, resulting in a 30% reduction in total nephron number in male sheep. Recently, we showed that uni-x males at 6 mo of age have elevated arterial pressure, reduced renal blood flow (RBF), glomerular filtration rate (GFR), and low plasma renin levels (Singh R, Denton K, Bertram J, Jefferies A, Head G, Lombardo P, Schneider-Kolsky M, Moritz K. J Hypertens 27: 386-396, 2009; Singh R, Denton K, Jefferies A, Bertram J, Moritz K. Clin Sci (Lond) 118: 669-680, 2010). We hypothesized this was due to upregulation of the intrarenal renin-angiotensin system (RAS). In this study, renal responses to ANG II infusion and ANG II type 1 receptor (AT1R) blockade were examined in the same 6-mo-old male sheep. Uni-x animals had reduced levels of renal tissue and plasma renin and ANG II. Renal gene expression of renin, and gene and protein levels of AT1R and AT2R, were significantly lower in uni-x animals. In response to graded ANG II infusion, sham animals had the expected decrease in conscious RBF and GFR. Interestingly, the response was biphasic in uni-x sheep, with GFR initially decreasing, but then increasing at higher ANG II doses (34 ± 7%; P(group × treatment) < 0.001), due to a paradoxical decrease in renal vascular resistance (P(group × treatment) < 0.001). In response to AT1R blockade, while GFR and RBF responded similarly between groups, there was a marked increase in sodium excretion in uni-x compared with sham sheep (209 ± 35 vs. 25 ± 12%; P < 0.001). In conclusion, in 6-mo-old male sheep born with a single kidney, these studies demonstrate that this is a low-renin form of hypertension, in which responses to ANG II are perturbed and the intrarenal RAS is downregulated.     

The novel phloroglucinol PMT7 kills glycolytic cancer cells by blocking autophagy and sensitizing to nutrient stress

The switch from oxidative phosphorylation to glycolytic metabolism results in cells that generate fewer reactive oxygen species (ROS) and are resistant to the intrinsic induction of apoptosis. As a consequence, glycolytic cancer cells are resistant to radiation and chemotherapeutic agents that rely on production of ROS or intrinsic apoptosis. Further, the level of glycolysis correlates with tumor invasion, making glycolytic cancer cells an important target for new therapy development. We have synthesized a novel redox-active quinone phloroglucinol derivative, PMT7. Toxicity of PMT7 was in part due to loss of mitochondrial membrane potential in treated cells with subsequent loss of mitochondrial metabolic activity. Mitochondrial gene knockout ρ0 cells, a model of highly glycolytic cancers, were only half as sensitive as the corresponding wild-type cells and metabolic pathways downstream of MET were unaffected in ρ0 cells. However, PMT7 toxicity was also due to a block in autophagy. Both wild-type and ρ0 cells were susceptible to autophagy blockade, and the resistance of ρ0 cells to PMT7 could be overcome by serum deprivation, a situation where autophagy becomes necessary for survival. The stress response class III deacetylase SIRT1 was not significantly involved in PMT7 toxicity, suggesting that unlike other chemotherapeutic drugs, SIRT1-mediated stress and survival responses were not induced by PMT7. The dependence on autophagy or other scavenging pathways makes glycolytic cancer cells vulnerable. This can be exploited by induction of energetic stress to specifically sensitize glycolytic cells to other stresses such as nutrient deprivation or potentially chemotherapy.     

Cold-adapted protease enables quantitation of surface proteins in the absence of membrane trafficking

We report here an improved method for analyzing protein surface expression utilizing a cold-adapted trypsin. Preservation of activity of the enzyme at 0-4°C permits modification of the protease method of surface analysis to temperatures at which trafficking of mammalian plasmalemmal proteins is blocked. This is an important advantage over established trypsin-cleavage protocols. Moreover, the method is less time-consuming than surface biotinylation.     

Diversity of natural enemies in Central Otago,New Zealand apple orchards: a practical measure of sustainability in pest management?

The diversity of the arthropod fauna in apple orchards in Central Otago was recorded from 1994 to 1999 using beating trays, pitfall traps, and sticky traps and the data analysed by the Shannon–Wiener Index. Three different fruit production systems were compared, conventional (CFP), integrated (IFP), and biological (BFP), to determine whether total arthropod diversity and/or the diversity of natural enemies (predators and parasitoids) could be used to measure the sustainability of their pest management practices. The contribution of natural enemies to the diversity indices was also examined to determine if they reflected the key species essential for sustainable pest management. The diversity of natural enemies in beating trays was found to be the measure most sensitive to changes in pest management. The diversity of both the total arthropod fauna and natural enemies was much lower under CFP than under either IFP or BFP, due to the use of broad-spectrum pesticides. This practice made the CFP programme unsustainable and it is no longer used. During the transition from CFP to IFP, the diversity indices rose to become similar to that in the BFP programme by the third season. The introduction of frequent applications of fungicides in BFP, including lime sulphur, appeared to reduce total arthropod and natural enemy diversity. Falls in the diversity indices for natural enemies were shown to reflect reduced numbers, range, and evenness of natural enemies but not necessarily the key species known to be critical for sustainable pest management. It is proposed that a Shannon–Wiener Index for natural enemies in beating trays of 0.2 or less in summer is strongly indicative of unsustainable pest management in Otago apple orchards. On the other hand, indices of 0.3–0.8, as found under IFP and BFP, do not give unequivocal or quantitative indications of the sustainability of pest management. A suite of other measures of sustainability are more useful, notably combining lower pesticide use, reduced pest damage and presence at harvest, the greater roles of key natural enemies, more effective plant resistance to pests and diseases, and higher profitability.     

Design and synthesis of novel amide AKT1 inhibitors with selectivity over CDK2

Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2).