Amphisomes: out of the autophagosome shadow?
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ABSTRACT:
SUBMITTER: Sanchez-Wandelmer J
PROVIDER: S-EPMC3981145 | biostudies-other | 2013 Dec
REPOSITORIES: biostudies-other
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Project description:Awareness toward the risks of blue light (BL) exposure is rising due to increased use of BL-enriched LEDs in displays. Short-wave BL (400-500 nm) has a high photochemical energy, leading to the enhanced production of reactive oxygen species (ROS). BL potentially plays a role in causing dry eye, cataracts, and age-related macular degeneration (AMD). The effect of BL on retinal pigment epithelium cells (RPEs) or photoreceptors has been extensively investigated. In contrast, only a few studies have investigated the effects of BL exposure on Müller cells (MCs). This is mainly due to their lack of photosensitive elements and the common assumption that their reaction to stress is only secondary in disease development. However, MCs perform important supportive, secretory, and immune functions in the retina, making them essential for retinal survival. Increased oxidative stress is a key player in many retinal diseases such as AMD or glaucoma. We hypothesize that increased oxidative stress can also affect MCs. Thus, we simulated oxidative stress levels by exposing primary porcine MCs and human MIO-M1 cells to BL. To confirm the wavelength-specificity, the cells were further exposed to red (RL), purple (PL), and white light (WL). BL and WL exposure increased ROS levels, but only BL exposure led to apoptosis in primary MCs. Thus, BL accounted for the harmful part of WL exposure. When cells were simultaneously exposed to BL and RL (i.e., PL), cell damage due to BL could be partly prevented, as could the inhibition of p53, demonstrating the protective effect of RL and p53 dependency. In contrast, BL hardly induced apoptosis in MIO-M1 cells, which is likely due to the immortalization of the cells. Therefore, enhanced oxidative stress levels can significantly harm MC function, probably leading to decreased retinal survival and, thus, further enhancing the progression of retinal diseases. Preventing the cell death of these essential retinal cells represents a promising therapy option to enhance retinal survival.
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Project description:Purpose of reviewThe last decade has witnessed tremendous advances in revealing an important role for the interleukin (IL)-17 cytokine family in the pathogenesis of spondyloarthritis (SpA). Although most attention has been focused on IL-17A, a potential role of other IL-17 family members in inflammation and tissue remodelling is emerging. Herein, I review recent studies covering the role of IL-17B-F cytokines in the pathogenesis of SpA.Recent findingsSeveral recent studies provided new insights into the cellular source, regulation and function of IL-17F. IL-17F/IL-17A expression ratio is higher in psoriatic skin compared to SpA synovitis. IL-17F-expressing T cells produce different proinflammatory mediators than IL-17A-expressing cells, and IL-17F and IL-17A signal through different receptor complex. Dual IL-17A and IL-17F neutralization resulted in greater suppression of downstream inflammatory and tissue remodelling responses. Furthermore, there is additional evidence of IL-23-independent IL-17 production. In contrast to IL-17A, IL-17F and IL-17C, which play proinflammatory roles in skin and joint inflammation, an anti-inflammatory function is proposed for IL-17D. An increase in IL-17E is associated with subclinical gut microbiome alterations after anti-IL-17A therapy in SpA patients.SummaryIL-17 family cytokines may act as agonists or antagonists to IL-17A contributing in concert to local inflammatory responses. Understanding their function and identifying their cellular sources, and molecular mechanisms driving their expression will be the key to designing rational therapies in SpA.
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Project description:When an object casts a shadow on a background surface, both the offset of the shadow and the blur of its penumbra are potential cues to the distance between the object and the background. However, the shadow offset and blur are also affected by the direction and angular extent of the light source and these are often unknown. This means that the observer must make some assumptions about the illumination, the expected distribution of depth, or the relation between offset and depth in order to use shadows to make distance judgments. Here, we measure human judgments of perceived depth over a range of shadow offsets, blurs, and lighting directions to gain insight into this internal model. We find that distance judgments are relatively unaffected by blur or light direction, whereas the shadow offset has a strong and linear effect. The data are consistent with two models, a generic shadow-to-depth model and a Bayesian model.
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Project description:BACKGROUND:A large part of the long-term care is provided by non-professional caregivers, generally without any monetary payment but a value economic of time invested. The economic relevance of informal caregivers has been recognized in Spain; however, public provision may still be scarce. The objective of this paper is to estimate the economic burden associated with informal long-term care that should assume the families through a new concept of cost sharing that consider opportunity costs of time provided by informal caregivers. METHODS:The study sample includes all dependent adults in Spain. Socioeconomic information and the number of hours of informal care was collected through the Spanish Disability and Dependency Survey. The terms of shadow and extended shadow cost sharing were defined as the difference between the maximum potential amount of money that families could receive for the provision of informal care and the amount that actually they received and the value of informal care time with respect to the amount received, respectively. RESULTS:53.87% of dependent persons received an economic benefit associated to informal care. The average weekly hours of care were 71.59 (92.62 without time restrictions). Shadow cost sharing amounted to, on average, two thirds, whereas the State financed the remaining third. In terms of extended shadow cost sharing, the State financed between 3% and 10% of informal care provided by caregivers. CONCLUSIONS:This study reveals the deficient support received for the provision of informal care in Spain. More than 90% of informal care time is not covered by the economic benefits that families receive from the State.
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Project description:OBJECTIVES:Feedback is a powerful learning tool, but a lack of appropriate feedback is a very common complaint from learners to teachers. To improve opportunities for feedback on objective structured clinical examinations (OSCEs), a modified examiner role, termed the "shadow" examiner, was tested. This study aims to present and analyze comparisons between the "shadow" examiner and the original OSCE examiner format. METHODS:In 2011, experiments were carried out with modifications to the examiner's role to define the "shadow" examiner format. From February 2012 to May 2014, research was conducted with 415 6th-year medical students. Of these students, 316 were randomly assigned to assessments by both "shadow" and "fixed" examiners. Pearson correlation analysis with linear regression, Student's t-tests and Bland-Altman plots were the statistical methods used to compare the assessment modes. To strengthen the analysis, checklist items were classified by domain. RESULTS:High correlations between the "shadow" and "fixed" examiners' global scores were observed. The results of the analysis of specific domains demonstrated higher correlations for cognitive scores and lower correlations for affective scores. No statistically significant differences between the mean examiner global scores were found. The Bland-Altman analysis showed that the "shadow" examiners' affective scores were significantly higher than those of the "fixed" examiners, but the magnitude of this difference was small. CONCLUSION:The modified examiner role did not lead to any important bias in the students' scores compared with the original OSCE examiner format. This new strategy may provide important insights for formative assessments of clinical performance.
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Project description:Macroautophagy/autophagy is a proteolytic pathway that is involved in both bulk degradation of cytoplasmic proteins as well as in selective degradation of cytoplasmic organelles. Autophagic flux is often defined as a measure of autophagic degradation activity, and many techniques exist to assess autophagic flux. Although these techniques have generated invaluable information about the autophagic system, the quest continues for developing methods that not only enhance sensitivity and provide a means of quantification, but also accurately reflect the dynamic character of the pathway. Based on the theoretical framework of metabolic control analysis, where the autophagosome flux is the quantitative description of the rate a flow along a pathway, here we treat the autophagy system as a multi-step pathway. We describe a single-cell fluorescence live-cell imaging-based approach that allows the autophagosome flux to be accurately measured. This method characterizes autophagy in terms of its complete autophagosome and autolysosome pool size, the autophagosome flux, J, and the transition time, τ, for autophagosomes and autolysosomes at steady state. This approach provides a sensitive quantitative method to measure autophagosome flux, pool sizes and transition time in cells and tissues of clinical relevance. ABBREVIATIONS:ATG5/APG5, autophagy-related 5; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; J, flux; MEF, mouse embryonic fibroblast; MTOR, mechanistic target of rapamycin kinase; nA, number of autophagosomes; nAL, number of autolysosomes; nL, number of lysosomes; p-MTOR, phosphorylated mechanistic target of rapamycin kinase; RFP, red fluorescent protein; siRNA, small interfering RNA; τ, transition time; TEM, transmission electron microscopy.
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Project description:Killing is perhaps the most definite form of communication possible. Microbes such as yeasts and gut bacteria have been shown to exhibit killer phenotypes. The killer strains are able to kill other microbes occupying the same ecological niche, and do so with impunity. It would therefore be expected that, wherever a killer phenotype has arisen, all members of the population would soon be killers or dead. Surprisingly, (1) one can find both killer and sensitive strains in coexistence, both in the wild and in in vitro experiments, and (2) the absolute fitness cost of the killer phenotype often seems to be very small. We present an explicit model of such coexistence in a fragmented or discrete environment. A killer strain may kill all sensitive cells in one patch (one piece of rotting fruit, one cave or one human gut, for example), allowing sensitives to exist only in the absence of killer strains on the same patch. In our model, populations spread easily between patches, but in a stochastic manner: one can imagine spores borne by the wind over a field of untended apple trees, or enteric disease transmission in a region in which travel is effectively unrestricted. What we show is that coexistence is not only possible, but that it is possible even if the absolute fitness advantage of the sensitive strain over the killer strain is arbitrarily small. We do this by performing a specifically targeted mathematical analysis on our model, rather than via simulations. Our model does not assume large population densities, and may thus be useful in the context of understanding the ecology of extreme environments.
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Project description:Critical developmental control genes sometimes contain "shadow" enhancers that can be located in remote positions, including the introns of neighboring genes [1]. They nonetheless produce patterns of gene expression that are the same as or similar to those produced by more proximal primary enhancers. It was suggested that shadow enhancers help foster robustness in gene expression in response to environmental or genetic perturbations [2, 3]. We critically tested this hypothesis by employing a combination of bacterial artificial chromosome (BAC) recombineering and quantitative confocal imaging methods [2, 4]. Evidence is presented that the snail gene is regulated by a distal shadow enhancer located within a neighboring locus. Removal of the proximal primary enhancer does not significantly perturb snail function, including the repression of neurogenic genes and formation of the ventral furrow during gastrulation at normal temperatures. However, at elevated temperatures, there is sporadic loss of snail expression and coincident disruptions in gastrulation. Similar defects are observed at normal temperatures upon reductions in the levels of Dorsal, a key activator of snail expression (reviewed in [5]). These results suggest that shadow enhancers represent a novel mechanism of canalization whereby complex developmental processes "bring about one definite end-result regardless of minor variations in conditions" [6].
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Project description:Autophagy, a major clearance route for many long-lived proteins and organelles, has long been implicated in cancer development. Myc is a proto-oncogene often found to be deregulated in many cancers, and thus is an attractive target for design of cancer therapy. Therefore, understanding the relationship between anti-Myc strategies and autophagy will be important for development of effective therapy. Here, we show that Myc depletion inhibits autophagosome formation and impairs clearance of autophagy substrates. Myc suppression has an inhibitory effect on autophagy via reduction of c-Jun N-terminal kinase 1 (JNK1) and B-cell lymphoma 2 (Bcl2) phosphorylation. Additionally, the decrease in JNK1 phosphorylation observed with Myc knockdown is associated with a reduction in ROS production. Our data suggest that targeting Myc in cancer therapy might have the additional benefit of inhibiting autophagy in the case of therapy resistance associated with chemotherapy-induced autophagy.
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