Interrelations between BID and cyclophilins in the mitochondrial apoptotic pathway.

The BH3-only BCL-2 protein BID is thought, in some cases, to be responsible for the initiation of cytochrome c release from mitochondria during apoptosis. In order to study this process in an in vitro system, the rat Bid gene was cloned, recombinant BID purified, and truncated BID (tBID) produced. Additionally, reliable procedures were developed for the isolation of intact mitochondria from a rat neuroblastoma cell line and for assay of cytochrome c release from the isolated mitochondria. The involvement of the permeability transition (widely regarded as a mechanism for mitochondrial permeabilisation and/or remodelling during cytochrome c release) was investigated. However, using mitochondrially entrapped fluorophores and agents that promote the transition (Ca2+, overexpression of mitochondrial cyclophilin D), BID-induced cytochrome c release was in fact found to be independent of permeability transition. Nevertheless, CSA, a potent inhibitor of cyclophilins and the permeability transition, did inhibit cytochrome c release. To resolve the action of CSA, a kinetic model of tBID-induced cytochrome c release was formulated from first principles. This considered tBID-induced oligomerisation and auto-oligomerisation of the BAK protein into BAK pores and efflux of cytochrome c via these pores. The model was based on previously published data and the presence of BAK, but not BAX, in the isolated mitochondria. Analysis according to this model indicated that the formation of pores, rather than efflux through pores, was inhibited by CSA. Direct measurements of tBID-induced change in BAK conformation (an essential step in oligomerisation) by trypsin cleavage confirmed that CSA inhibited this step. As potential targets of CSA, the isolated mitochondria contained both cyclophilin D (mitochondrial matrix) and residual cyclophilin A (a cytosolic enzyme). However neither cyclophilin D (overexpression) nor cyclophilin A (addition of recombinant enzyme) stimulated cytochrome c release. Moreover, DB25, a CSA analogue that inhibits the catalytic activity of both cyclophilins, but does not allow interaction with downstream targets such as calcineurin, was ineffective, and instead had a stimulatory effect on cytochrome c release. It appeared therefore that the cyclophilin-CSA complex may be the inhibitory species. However inhibition was not attributable to calcineurin inhibition, as judged by 32P labelling and the effects of Ca2+. It is concluded that the cyclophilin-CSA complex may inhibit BAK conformational change by a novel mechanism. Two other novel findings arose in the course of the study, namely a 54 kD proline-rich cyclophilin D binding protein (identified by pull-downs and mass spectrometry) and phosphorylation of a (non- identified) 17 kD protein in cyclophilin D overexpressing mitochondria

Review: Consumption-stage food waste reduction interventions - What works and how to design better interventions

Food waste prevention has become an issue of international concern, with Sustainable Development Goal 12.3 aiming to halve per capita global food waste at the retail and consumer levels by 2030. However there is no review that has considered the effectiveness of interventions aimed at preventing food waste in the consumption stages of the food system. This significant gap, if filled, could help support those working to reduce food waste in the developed world, providing knowledge of what interventions are specifically effective at preventing food waste. This paper fills this gap, identifying and summarizing food-waste prevention interventions at the consumption/consumer stage of the supply chain via a rapid review of global academic literature from 2006 to 2017. We identify 17 applied interventions that claim to have achieved food waste reductions. Of these, 13 quantified food waste reductions. Interventions that changed the size or type of plates were shown to be effective (up to 57% food waste reduction) in hospitality environments. Changing nutritional guidelines in schools were reported to reduce vegetable waste by up to 28%, indicating that healthy diets can be part of food waste reduction strategies. Information campaigns were also shown to be effective with up to 28% food waste reduction in a small sample size intervention. Cooking classes, fridge cameras, food sharing apps, advertising and information sharing were all reported as being effective but with little or no robust evidence provided. This is worrying as all these methods are now being proposed as approaches to reduce food waste and, except for a few studies, there is no reproducible quantified evidence to assure credibility or success. To strengthen current results, a greater number of longitudinal and larger sample size intervention studies are required. To inform future intervention studies, this paper proposes a standardised guideline, which consists of: (1) intervention design; (2) monitoring and measurement; (3) moderation and mediation; (4) reporting; (5) systemic effects. Given the importance of food-waste reduction, the findings of this review highlight a significant evidence gap, meaning that it is difficult to make evidence-based decisions to prevent or reduce consumption-stage food waste in a cost-effective manner

A Comparative Study of Three Different Types of Stem Cells for Treatment of Rat Spinal Cord Injury

Three different sources of human stem cells-bone marrow-derived mesenchymal stem cells (BM-MSCs), neural progenitors (NPs) derived from immortalized spinal fetal cell line (SPC-01), and induced pluripotent stem cells (iPSCs)-were compared in the treatment of a balloon-induced spinal cord compression lesion in rats. One week after lesioning, the rats received either BM-MSCs (intrathecally) or NPs (SPC-01 cells or iPSC-NPs, both intraspinally), or saline. The rats were assessed for their locomotor skills (BBB, flat beam test, and rotarod). Morphometric analyses of spared white and gray matter, axonal sprouting, and glial scar formation, as well as qPCR and Luminex assay, were conducted to detect endogenous gene expression, while inflammatory cytokine levels were performed to evaluate the host tissue response to stem cell therapy. The highest locomotor recovery was observed in iPSC-NP-grafted animals, which also displayed the highest amount of preserved white and gray matter. Grafted iPSC-NPs and SPC-01 cells significantly increased the number of growth-associated protein 43 (GAP43+) axons, reduced astrogliosis, downregulated Casp3 expression, and increased IL-6 and IL-12 levels. hMSCs transiently decreased levels of inflammatory IL-2 and TNF-alpha. These findings correlate with the short survival of hMSCs, while NPs survived for 2 months and matured slowly into glia- and tissue-specific neuronal precursors. SPC-01 cells differentiated more in astroglial phenotypes with a dense structure of the implant, whereas iPSC-NPs displayed a more neuronal phenotype with a loose structure of the graft. We concluded that the BBB scores of iPSC-NP- and hMSC-injected rats were superior to the SPC-01-treated group. The iPSC-NP treatment of spinal cord injury (SCI) provided the highest recovery of locomotor function due to robust graft survival and its effect on tissue sparing, reduction of glial scarring, and increased axonal sprouting

Video decision support tool for advance care planning in dementia: randomised controlled trial

Objective To evaluate the effect of a video decision support tool on the preferences for future medical care in older people if they develop advanced dementia, and the stability of those preferences after six weeks

Public understandings of addiction: where do neurobiological explanations fit?

Developments in the field of neuroscience, according to its proponents, offer the prospect of an enhanced understanding and treatment of addicted persons. Consequently, its advocates consider that improving public understanding of addiction neuroscience is a desirable aim. Those critical of neuroscientific approaches, however, charge that it is a totalising, reductive perspective–one that ignores other known causes in favour of neurobiological explanations. Sociologist Nikolas Rose has argued that neuroscience, and its associated technologies, are coming to dominate cultural models to the extent that 'we' increasingly understand ourselves as 'neurochemical selves'. Drawing on 55 qualitative interviews conducted with members of the Australian public residing in the Greater Brisbane area, we challenge both the 'expectational discourses' of neuroscientists and the criticisms of its detractors. Members of the public accepted multiple perspectives on the causes of addiction, including some elements of neurobiological explanations. Their discussions of addiction drew upon a broad range of philosophical, sociological, anthropological, psychological and neurobiological vocabularies, suggesting that they synthesised newer technical understandings, such as that offered by neuroscience, with older ones. Holding conceptual models that acknowledge the complexity of addiction aetiology into which new information is incorporated suggests that the impact of neuroscientific discourse in directing the public's beliefs about addiction is likely to be more limited than proponents or opponents of neuroscience expect

Operationalizing frailty among older residents of assisted living facilities

<p>Abstract</p> <p>Background</p> <p>Frailty in later life is viewed as a state of heightened vulnerability to poor outcomes. The utility of frailty as a measure of vulnerability in the assisted living (AL) population remains unexplored. We examined the feasibility and predictive accuracy of two different interpretations of the Cardiovascular Health Study (CHS) frailty criteria in a population-based sample of AL residents.</p> <p>Methods</p> <p>CHS frailty criteria were operationalized using two different approaches in 928 AL residents from the Alberta Continuing Care Epidemiological Studies (ACCES). Risks of one-year mortality and hospitalization were estimated for those categorized as frail or pre-frail (compared with non-frail). The prognostic significance of individual criteria was explored, and the area under the ROC curve (AUC) was calculated for select models to assess the utility of frailty in predicting one-year outcomes.</p> <p>Results</p> <p>Regarding feasibility, complete CHS criteria could not be assessed for 40% of the initial 1,067 residents. Consideration of supplementary items for select criteria reduced this to 12%. Using absolute (CHS-specified) cut-points, 48% of residents were categorized as frail and were at greater risk for death (adjusted risk ratio [RR] 1.75, 95% CI 1.08-2.83) and hospitalization (adjusted RR 1.54, 95% CI 1.20-1.96). Pre-frail residents defined by absolute cut-points (48.6%) showed no increased risk for mortality or hospitalization compared with non-frail residents. Using relative cut-points (derived from AL sample), 19% were defined as frail and 55% as pre-frail and the associated risks for mortality and hospitalization varied by sex. Frail (but not pre-frail) women were more likely to die (RR 1.58 95% CI 1.02-2.44) and be hospitalized (RR 1.53 95% CI 1.25-1.87). Frail and pre-frail men showed an increased mortality risk (RR 3.21 95% CI 1.71-6.00 and RR 2.61 95% CI 1.40-4.85, respectively) while only pre-frail men had an increased risk of hospitalization (RR 1.58 95% CI 1.15-2.17). Although incorporating either frailty measure improved the performance of predictive models, the best AUCs were 0.702 for mortality and 0.633 for hospitalization.</p> <p>Conclusions</p> <p>Application of the CHS criteria for frailty was problematic and only marginally improved the prediction of select adverse outcomes in AL residents. Development and validation of alternative approaches for detecting frailty in this population, including consideration of female/male differences, is warranted.</p

Chimpanzee APOBEC3 proteins deter SIVs from any monkey business

Cross-species transmissions of viruses from animals to humans are at the origin of major human pathogenic viruses. While the role of ecological and epidemiological factors in the emergence of new pathogens is well documented, the importance of host factors is often unknown. Chimpanzees are the closest relatives of humans and the animal reservoir at the origin of the human AIDS pandemic. However, despite being regularly exposed to monkey lentiviruses through hunting, chimpanzees are naturally infected by only a single simian immunodeficiency virus, SIVcpz. Here, we asked why chimpanzees appear to be protected against the successful emergence of other SIVs. In particular, we investigated the role of the chimpanzee APOBEC3 genes in providing a barrier to infection by most monkey lentiviruses. We found that most SIV Vifs, including Vif from SIVwrc infecting western-red colobus, the chimpanzee's main monkey prey in West Africa, could not antagonize chimpanzee APOBEC3G. Moreover, chimpanzee APOBEC3D, as well as APOBEC3F and APOBEC3H, provided additional protection against SIV Vif antagonism. Consequently, lentiviral replication in primary chimpanzee CD4(+) T cells was dependent on the presence of a lentiviral vif gene that could antagonize chimpanzee APOBEC3s. Finally, by identifying and functionally characterizing several APOBEC3 gene polymorphisms in both common chimpanzees and bonobos, we found that these ape populations encode APOBEC3 proteins that are uniformly resistant to antagonism by monkey lentiviruses

Frailty Intervention Trial (FIT)

<p>Abstract</p> <p>Background</p> <p>Frailty is a term commonly used to describe the condition of an older person who has chronic health problems, has lost functional abilities and is likely to deteriorate further. However, despite its common use, only a small number of studies have attempted to define the syndrome of frailty and measure its prevalence. The criteria Fried and colleagues used to define the frailty syndrome will be used in this study (i.e. weight loss, fatigue, decreased grip strength, slow gait speed, and low physical activity). Previous studies have shown that clinical outcomes for frail older people can be improved using multi-factorial interventions such as comprehensive geriatric assessment, and single interventions such as exercise programs or nutritional supplementation, but no interventions have been developed to specifically reverse the syndrome of frailty.</p> <p>We have developed a multidisciplinary intervention that specifically targets frailty as defined by Fried et al. We aim to establish the effects of this intervention on frailty, mobility, hospitalisation and institutionalisation in frail older people.</p> <p>Methods and Design</p> <p>A single centre randomised controlled trial comparing a multidisciplinary intervention with usual care. The intervention will target identified characteristics of frailty, functional limitations, nutritional status, falls risk, psychological issues and management of chronic health conditions. Two hundred and thirty people aged 70 and over who meet the Fried definition of frailty will be recruited from clients of the aged care service of a metropolitan hospital. Participants will be followed for a 12-month period.</p> <p>Discussion</p> <p>This research is an important step in the examination of specifically targeted frailty interventions. This project will assess whether an intervention specifically targeting frailty can be implemented, and whether it is effective when compared to usual care. If successful, the study will establish a new approach to the treatment of older people at risk of further functional decline and institutionalisation. The strategies to be examined are readily transferable to routine clinical practice and are applicable broadly in the setting of aged care health services.</p> <p>Trial Registration</p> <p>Australian New Zealand Clinical Trails Registry: ACTRN12608000250336.</p