CCT complex restricts neuropathogenic protein aggregation via autophagy

Aberrant protein aggregation is controlled by various chaperones, including CCT (chaperonin containing TCP-1)/TCP-1/TRiC. Mutated CCT4/5 subunits cause sensory neuropathy and CCT5 expression is decreased in Alzheimer's disease. Here, we show that CCT integrity is essential for autophagosome degradation in cells or Drosophila and this phenomenon is orchestrated by the actin cytoskeleton. When autophagic flux is reduced by compromise of individual CCT subunits, various disease-relevant autophagy substrates accumulate and aggregate. The aggregation of proteins like mutant huntingtin, ATXN3 or p62 after CCT2/5/7 depletion is predominantly autophagy dependent, and does not further increase with CCT knockdown in autophagy-defective cells/organisms, implying surprisingly that the effect of loss-of-CCT activity on mutant ATXN3 or huntingtin oligomerization/aggregation is primarily a consequence of autophagy inhibition rather than loss of physiological anti-aggregation activity for these proteins. Thus, our findings reveal an essential partnership between two key components of the proteostasis network and implicate autophagy defects in diseases with compromised CCT complex activity.We are grateful to the Wellcome Trust (Principal Research Fellowship to DCR (095317/Z/11/Z)), a Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), NIHR Biomedical Research Unit in Dementia at Addenbrooke’s Hospital, the Treat PolyQ project (European community’s Seventh Framework Programme under grant agreement No 264508) and the Wellcome Trust/MRC strategic grant for neurodegeneration (D.C.R. and C.J.O.'K.) for funding. DCC was supported by an Alzheimer’s Research U.K. Senior Research Fellowship (ART-SRF2010-2) and by the Wellcome Trust (082604/2/07/Z)

NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells

Green Production of Anionic Surfactant Obtained from Pea Protein

A pea protein isolate was hydrolyzed by a double enzyme treatment method in order to obtain short peptide sequences used as raw materials to produce lipopeptides-based surfactants. Pea protein hydrolysates were prepared using the combination of Alcalase and Flavourzyme. The influence of the process variables was studied to optimize the proteolytic degradation to high degrees of hydrolysis. The average peptide chain lengths were obtained at 3–5 amino acid units after a hydrolysis of 30 min with the mixture of enzymes. Then, N-acylation in water, in presence of acid chloride (C12 and C16), carried out with a conversion rate of amine functions of 90%, allowed to obtain anionic surfactant mixtures (lipopeptides and sodium fatty acids). These two steps were performed in water, in continuous and did not generate any waste. This process was therefore in line with green chemistry principles. The surface activities (CMC, foaming and emulsifying properties) of these mixtures were also studied. These formulations obtained from natural renewable resources and the reactions done under environmental respect, could replace petrochemical based surfactants for some applications

Dicationic Alkylammonium Bromide Gemini Surfactants. Membrane Perturbation and Skin Irritation

Dicationic alkylammonium bromide gemini surfactants represent a class of amphiphiles potentially effective as skin permeation enhancers. However, only a limited number of studies has been dedicated to the evaluation of the respective cytotoxicity, and none directed to skin irritation endpoints. Supported on a cell viability study, the cytotoxicity of gemini surfactants of variable tail and spacer length was assessed. For this purpose, keratinocyte cells from human skin (NCTC 2544 cell line), frequently used as a model for skin irritation, were employed. The impact of the different gemini surfactants on the permeability and morphology of model vesicles was additionally investigated by measuring the leakage of calcein fluorescent dye and analyzing the NMR spectra of 31P, respectively. Detail on the interaction of gemini molecules with model membranes was also provided by a systematic differential scanning calorimetry (DSC) and molecular dynamics (MD) simulation. An irreversible impact on the viability of the NCTC 2544 cell line was observed for gemini concentrations higher than 25 mM, while no cytotoxicity was found for any of the surfactants in a concentration range up to 10 mM. A higher cytotoxicity was also found for gemini surfactants presenting longer spacer and shorter tails. The same trend was obtained in the calorimetric and permeability studies, with the gemini of longest spacer promoting the highest degree of membrane destabilization. Additional structural and dynamical characterization of the various systems, obtained by 31P NMR and MD, provide some insight on the relationship between the architecture of gemini surfactants and the respective perturbation mechanism

Evidence-based practice educational intervention studies: A systematic review of what is taught and how it is measured

Abstract Background Despite the established interest in evidence-based practice (EBP) as a core competence for clinicians, evidence for how best to teach and evaluate EBP remains weak. We sought to systematically assess coverage of the five EBP steps, review the outcome domains measured, and assess the properties of the instruments used in studies evaluating EBP educational interventions. Methods We conducted a systematic review of controlled studies (i.e. studies with a separate control group) which had investigated the effect of EBP educational interventions. We used citation analysis technique and tracked the forward and backward citations of the index articles (i.e. the systematic reviews and primary studies included in an overview of the effect of EBP teaching) using Web of Science until May 2017. We extracted information on intervention content (grouped into the five EBP steps), and the outcome domains assessed. We also searched the literature for published reliability and validity data of the EBP instruments used. Results Of 1831 records identified, 302 full-text articles were screened, and 85 included. Of these, 46 (54%) studies were randomised trials, 51 (60%) included postgraduate level participants, and 63 (75%) taught medical professionals. EBP Step 3 (critical appraisal) was the most frequently taught step (63 studies; 74%). Only 10 (12%) of the studies taught content which addressed all five EBP steps. Of the 85 studies, 52 (61%) evaluated EBP skills, 39 (46%) knowledge, 35 (41%) attitudes, 19 (22%) behaviours, 15 (18%) self-efficacy, and 7 (8%) measured reactions to EBP teaching delivery. Of the 24 instruments used in the included studies, 6 were high-quality (achieved ≥3 types of established validity evidence) and these were used in 14 (29%) of the 52 studies that measured EBP skills; 14 (41%) of the 39 studies that measured EBP knowledge; and 8 (26%) of the 35 studies that measured EBP attitude. Conclusions Most EBP educational interventions which have been evaluated in controlled studies focus on teaching only some of the EBP steps (predominantly critically appraisal of evidence) and did not use high-quality instruments to measure outcomes. Educational packages and instruments which address all EBP steps are needed to improve EBP teaching

Eating Behavior, Physical Activity and Exercise Training: A Randomized Controlled Trial in Young Healthy Adults

Regular physical activity (PA) is an important part of the treatment of several medical conditions, including overweight and obesity, in which there may be a weakened appetite control. Eating behaviour traits influence weight control and may be different in active and sedentary subjects. This paper reports the relationships between the time spent in sedentary behaviour and physical activity (PA) of different intensity, and eating behaviour traits in young, healthy adults. Additionally, it reports the results of a six-month-long, randomized, controlled trial to examine the effect of an exercise intervention on eating behaviour traits. A total of 139 young (22.06 ± 2.26 years) healthy adults (68.35% women) with a Body Mass Index (BMI) of 24.95 ± 4.57 kg/m2 were enrolled. Baseline assessments of habitual PA were made using wrist-worn triaxial accelerometers; eating behaviour traits were examined via the self-reported questionnaires: Binge Eating, Three-Factor Eating Questionnaire-R18 and Control of Eating Questionnaire. The subjects were then randomly assigned to one of three groups: control (usual lifestyle), moderate-intensity exercise (aerobic and resistance training 3¨C4 days/week at a heart rate equivalent to 60% of the heart rate reserve (HRres) for the aerobic component, and at 50% of the 1 repetition maximum (RM) for the resistance component), or vigorous-intensity exercise (the same training but at 80% HRres for half of the aerobic training, and 70% RM for the resistance training). At baseline, sedentary behaviour was inversely associated with binge eating (r = −0.181, p < 0.05) and with uncontrolled eating (r = −0.286, p = 0.001). Moderate PA (MPA) was inversely associated with craving control (r = −0.188, p < 0.05). Moderate-to-vigorous PA (MVPA) was directly associated with binge eating (r = 0.302, p < 0.001) and uncontrolled eating (r = 0.346, p < 0.001), and inversely associated with craving control (r = −0.170, p < 0.015). Overall, PA was directly associated with binge eating (r = 0.275, p = 0.001), uncontrolled eating (r = 0.321, p < 0.001) and emotional eating (r = 0.204, p < 0.05). Additionally, only emotional eating was modified by the intervention, increasing in the vigorous-intensity exercise group (p < 0.05). In summary, we observed that time spent in sedentary behaviour/PA of different intensity is associated with eating behaviour traits, especially binge eating in young adults. In contrast, the six-month exercise intervention did not lead to appreciable changes in eating behaviour traits

Allopurinol Reduces the Lethality Associated with Acute Renal Failure Induced by Crotalus durissus terrificus Snake Venom: Comparison with Probenecid

In Brazil, among registered snake bites, those by the genus Crotalus originate the highest mortality rate. The rattlesnake Crotalus durissus terrificus is the most frequently implicated in these accidents. The kidney is a particularly vulnerable organ to the venom of this rattlesnake. In fact, the most serious complication of Crotalus snake bite is the renal dysfunction, and among the fatal cases of Crotalus bites in Brazil 5% are patients treated with antivenom. The hyperuricemia has been observed in human accidents with snake venoms, but this parameter has not received any special attention as a relevant factor in the etiology of renal dysfunction caused by these venoms. This study examined the effects of treatments with low-cost and low-risk uricostatic (allopurinol) and uricosuric (probenecid) drugs on the envenomation by C. d. terrificus, showing that allopurinol and probenecid mitigated certain nephrotoxic effects, as well as the survival of envenomed mice was improved through the effects of allopurinol on reduction of oxidative stress and intracellular formation of uric acid. This new knowledge provides consistent evidences linking uric acid with the renal dysfunction induced by rattlesnake bites and that the allopurinol deserves to be clinically evaluated as an approach complementary to anti-snake venom serotherapy

Disorder Effects on Exciton-Polariton Condensates

The impact of a random disorder potential on the dynamical properties of Bose Einstein condensates is a very wide research field. In microcavities, these studies are even more crucial than in the condensates of cold atoms, since random disorder is naturally present in the semiconductor structures. In this chapter, we consider a stable condensate, defined by a chemical potential, propagating in a random disorder potential, like a liquid flowing through a capillary. We analyze the interplay between the kinetic energy, the localization energy, and the interaction between particles in 1D and 2D polariton condensates. The finite life time of polaritons is taken into account as well. In the first part, we remind the results of [G. Malpuech et al. Phys. Rev. Lett. 98, 206402 (2007).] where we considered the case of a static condensate. In that case, the condensate forms either a glassy insulating phase at low polariton density (strong localization), or a superfluid phase above the percolation threshold. We also show the calculation of the first order spatial coherence of the condensate versus the condensate density. In the second part, we consider the case of a propagating non-interacting condensate which is always localized because of Anderson localization. The localization length is calculated in the Born approximation. The impact of the finite polariton life time is taken into account as well. In the last section we consider the case of a propagating interacting condensate where the three regimes of strong localization, Anderson localization, and superfluid behavior are accessible. The localization length is calculated versus the system parameters. The localization length is strongly modified with respect to the non-interacting case. It is infinite in the superfluid regime whereas it is strongly reduced if the fluid flows with a supersonic velocity.Comment: chapter for a book "Exciton Polaritons in Microcavities: New Frontiers" by Springer (2012), the original publication is available at http://www.springerlink.co

Migraine aura: retracting particle-like waves in weakly susceptible cortex

Cortical spreading depression (SD) has been suggested to underlie migraine aura. Despite a precise match in speed, the spatio-temporal patterns of SD and aura symptoms on the cortical surface ordinarily differ in aspects of size and shape. We show that this mismatch is reconciled by utilizing that both pattern types bifurcate from an instability point of generic reaction-diffusion models. To classify these spatio-temporal pattern we suggest a susceptibility scale having the value [sigma]=1 at the instability point. We predict that human cortex is only weakly susceptible to SD ([sigma]&#x3c;1), and support this prediction by directly matching visual aura symptoms with anatomical landmarks using fMRI retinotopic mapping. We discuss the increased dynamical repertoire of cortical tissue close to [sigma]=1, in particular, the resulting implications on migraine pharmacology that is hitherto tested in the regime ([sigma]&#x3e;&#x3e;1), and potentially silent aura occurring below a second bifurcation point at [sigma]=0 on the susceptible scale

What traits are carried on mobile genetic elements, and why?

Although similar to any other organism, prokaryotes can transfer genes vertically from mother cell to daughter cell, they can also exchange certain genes horizontally. Genes can move within and between genomes at fast rates because of mobile genetic elements (MGEs). Although mobile elements are fundamentally self-interested entities, and thus replicate for their own gain, they frequently carry genes beneficial for their hosts and/or the neighbours of their hosts. Many genes that are carried by mobile elements code for traits that are expressed outside of the cell. Such traits are involved in bacterial sociality, such as the production of public goods, which benefit a cell's neighbours, or the production of bacteriocins, which harm a cell's neighbours. In this study we review the patterns that are emerging in the types of genes carried by mobile elements, and discuss the evolutionary and ecological conditions under which mobile elements evolve to carry their peculiar mix of parasitic, beneficial and cooperative genes