Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy

Mitophagy orchestrates the autophagic degradation of dysfunctional mitochondria preventing their pathological accumulation and contributing to cellular homeostasis. We previously identified a novel chemical tool (hereafter referred to as PMI), which drives mitochondria into autophagy without collapsing their membrane potential (ΔΨm). PMI is an inhibitor of the protein-protein interaction (PPI) between the transcription factor Nrf2 and its negative regulator, Keap1 and is able to up-regulate the expression of autophagy-associated proteins, including p62/SQSTM1. Here we show that PMI promotes mitochondrial respiration, leading to a superoxide-dependent activation of mitophagy. Structurally distinct Keap1-Nrf2 PPI inhibitors promote mitochondrial turnover, while covalent Keap1 modifiers, including sulforaphane (SFN) and dimethyl fumarate (DMF), are unable to induce a similar response. Additionally, we demonstrate that SFN reverses the effects of PMI in co-treated cells by reducing the accumulation of p62 in mitochondria and subsequently limiting their autophagic degradation. This study highlights the unique features of Keap1-Nrf2 PPI inhibitors as inducers of mitophagy and their potential as pharmacological agents for the treatment of pathological conditions characterized by impaired mitochondrial quality control

Radial turbine cooling

Radial turbines have been used extensively in many applications including small ground based electrical power generators, automotive engine turbochargers and aircraft auxiliary power units. In all of these applications the turbine inlet temperature is limited to a value commensurate with the material strength limitations and life requirements of uncooled metal rotors. To take advantage of all the benefits that higher temperatures offer, such as increased turbine specific power output or higher cycle thermal efficiency, requires improved high temperature materials and/or blade cooling. Extensive research is on-going to advance the material properties of high temperature superalloys as well as composite materials including ceramics. The use of ceramics with their high temperature potential and low cost is particularly appealing for radial turbines. However until these programs reach fruition the only way to make significant step increases beyond the present material temperature barriers is to cool the radial blading

Color and texture associations in voice-induced synesthesia

Voice-induced synesthesia, a form of synesthesia in which synesthetic perceptions are induced by the sounds of people's voices, appears to be relatively rare and has not been systematically studied. In this study we investigated the synesthetic color and visual texture perceptions experienced in response to different types of “voice quality” (e.g., nasal, whisper, falsetto). Experiences of three different groups—self-reported voice synesthetes, phoneticians, and controls—were compared using both qualitative and quantitative analysis in a study conducted online. Whilst, in the qualitative analysis, synesthetes used more color and texture terms to describe voices than either phoneticians or controls, only weak differences, and many similarities, between groups were found in the quantitative analysis. Notable consistent results between groups were the matching of higher speech fundamental frequencies with lighter and redder colors, the matching of “whispery” voices with smoke-like textures, and the matching of “harsh” and “creaky” voices with textures resembling dry cracked soil. These data are discussed in the light of current thinking about definitions and categorizations of synesthesia, especially in cases where individuals apparently have a range of different synesthetic inducers

Kirschmann's Fourth Law

Kirschmann's Fourth Law states that the magnitude of simultaneous color contrast increases with the saturation of the inducing surround, but that the rate of increase reduces as saturation increases. Others since Kirschmann have agreed and disagreed. Here we show that the form of the relationship between simultaneous color contrast and inducer saturation depends on the method of measurement. Functions were measured by four methods: (i) asymmetric matching with a black surround, (ii) asymmetric matching with a surround metameric to equal energy white, (iii) dichoptic matching, and (iv) nulling an induced sinusoidal modulation. Results from the asymmetric matching conditions agreed with Kirschmann, whereas results from nulling and from dichoptic matching showed a more linear increase in simultaneous contrast with the saturation of the inducer. We conclude that the method certainly affects the conclusions reached, and that there may not be any "fair" way of measuring simultaneous contrast

Increasing Seed Viability of Maize Haploid Inducing Lines by Genetic and Non-Genetic Approaches

Some haploid inducing lines used in the production of maize doubled haploids (DHs), express germination problems and reduced vigor. In this study, haploid inducing lines RWS, RWK-76 and their reciprocal hybrids RWS/RWK-76 and RWK-76/RWS were examined for viability by Tetrazolium (TZ) and germination ability by standard germination tests. Evaluation based on TZ tests showed that 59% of the seed of RWK-76/RWS were not viable, compared with only 12% dead seed in RWS/RWK-76. Similarly, the percentage and speed of germination in RWK- 76/RWS (25%, 1.53) was lower than for RWS/RWK-76 (74%, 4.30). In an effort to develop a quick method for assessing seed viability in these lines, the TZ test was repeated in a different way. Seed from each genotype was placed in beakers containing distilled water.Seed would either float or sink. Subsequent TZ testing confirmed that seed that floated was dead, and seed that sank was alive, although some of them had defective embryos. The dead seed in both genotypes failed to develop an embryo, leaving an empty cavity that would fill with air and cause seed to float on water. This feature can be exploited for a simple and practical method to separate living from dead seed. In addition, we surveyed theig1 (indeterminate gametophyte) gene as a candidate for germination problems in inducer lines.Sequencing data from theig1 region showed that RWS and RWK-76 differed in one nucleotide and amino acidin the firstexon of ig1.Segregation of ig1 alleles from RWS and RWK-76 wassignificantly (P=0.01) distortedin the respectiveF2 population relative to the expected Mendelian segregation ratio (1:2:1). Thus, either ig1 or a linked gene in the ig1 region affect seed viability

Novel Inducers of the Envelope Stress Response BaeSR in Salmonella Typhimurium: BaeR Is Critically Required for Tungstate Waste Disposal

The RpoE and CpxR regulated envelope stress responses are extremely important for SalmonellaTyphimurium to cause infection in a range of hosts. Until now the role for BaeSR in both the Salmonella Typhimurium response to stress and its contribution to infection have not been fully elucidated. Here we demonstrate stationary phase growth, iron and sodium tungstate as novel inducers of the BaeRregulon, with BaeR critically required for Salmonella resistance to sodium tungstate. We show that functional overlap between the resistance nodulation-cell division (RND) multidrug transporters, MdtA, AcrD and AcrB exists for the waste disposal of tungstate from the cell. We also point to a role for enterobactinsiderophores in the protection of enteric organisms from tungstate, akin to the scenario in nitrogen fixing bacteria. Surprisingly, BaeR is the first envelope stress response pathway investigated in S. Typhimurium that is not required for murine typhoid in either ityS or ityR mouse backgrounds. BaeR is therefore either required for survival in larger mammals such as pigs or calves, an avian host such as chickens, or survival out with the host altogether where Salmonella and related enterics must survive in soil and water

Transcriptional regulatory networks controlling woolliness in peach in response to preharvest gibberellin application and cold storage

BACKGROUND: Postharvest fruit conservation relies on low temperatures and manipulations of hormone metabolism to maintain sensory properties. Peaches are susceptible to chilling injuries, such as ‘woolliness’ that is caused by juice loss leading to a ‘wooly’ fruit texture. Application of gibberellic acid at the initial stages of pit hardening impairs woolliness incidence, however the mechanisms controlling the response remain unknown. We have employed genome wide transcriptional profiling to investigate the effects of gibberellic acid application and cold storage on harvested peaches. RESULTS: Approximately half of the investigated genes exhibited significant differential expression in response to the treatments. Cellular and developmental process gene ontologies were overrepresented among the differentially regulated genes, whereas sequences in cell death and immune response categories were underrepresented. Gene set enrichment demonstrated a predominant role of cold storage in repressing the transcription of genes associated to cell wall metabolism. In contrast, genes involved in hormone responses exhibited a more complex transcriptional response, indicating an extensive network of crosstalk between hormone signaling and low temperatures. Time course transcriptional analyses demonstrate the large contribution of gene expression regulation on the biochemical changes leading to woolliness in peach. CONCLUSION: Overall, our results provide insights on the mechanisms controlling the complex phenotypes associated to postharvest textural changes in peach and suggest that hormone mediated reprogramming previous to pit hardening affects the onset of chilling injuries. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12870-015-0659-2) contains supplementary material, which is available to authorized users

Protective Activity of Broccoli Sprout Juice in a Human Intestinal Cell Model of Gut Inflammation

Benefits to health from a high consumption of fruits and vegetables are well established and have been attributed to bioactive secondary metabolites present in edible plants. However, the effects of specific health-related phytochemicals within a complex food matrix are difficult to assess. In an attempt to address this problem, we have used elicitation to improve the nutraceutical content of seedlings of Brassica oleracea grown under controlled conditions. Analysis, by LC-MS, of the glucosinolate, isothiocyanate and phenolic compound content of juices obtained from sprouts indicated that elicitation induces an enrichment of several phenolics, particularly of the anthocyanin fraction. To test the biological activity of basal and enriched juices we took advantage of a recently developed in vitro model of inflamed human intestinal epithelium. Both sprouts’ juices protected intestinal barrier integrity in Caco-2 cells exposed to tumor necrosis factor under marginal zinc deprivation, with the enriched juice showing higher protection. Multivariate regression analysis indicated that the extent of rescue from stress-induced epithelial dysfunction correlated with the composition in bioactive molecules of the juices and, in particular, with a group of phenolic compounds, including several anthocyanins, quercetin-3-Glc, cryptochlorogenic, neochlorogenic and cinnamic acids

Trolox and ascorbic acid reduce direct and indirect oxidative stress in the IPEC-J2 cells, an in vitro model for the porcine gastrointestinal tract

Oxidative stress in the small intestinal epithelium is a major cause of barrier malfunction and failure to regenerate. This study presents a functional in vitro model using the porcine small intestinal epithelial cell line IPEC-J2 to examine the effects of oxidative stress and to estimate the antioxidant and regenerative potential of Trolox, ascorbic acid and glutathione monoethyl ester. Hydrogen peroxide and diethyl maleate affected the tight junction (zona occludens-1) distribution, significantly increased intracellular oxidative stress (CM-H(2)DCFDA) and decreased the monolayer integrity (transepithelial electrical resistance and FD-4 permeability), viability (neutral red) and wound healing capacity (scratch assay). Trolox (2 mM) and 1 mM ascorbic acid pre-treatment significantly reduced intracellular oxidative stress, increased wound healing capacity and reduced FD-4 permeability in oxidatively stressed IPEC-J2 cell monolayers. All antioxidant pre-treatments increased transepithelial electrical resistance and viability only in diethyl maleate-treated cells. Glutathione monoethyl ester (10 mM) pretreatment significantly decreased intracellular oxidative stress and monolayer permeability only in diethyl maleate-treated cells. These data demonstrate that the IPEC-J2 oxidative stress model is a valuable tool to screen antioxidants before validation in piglets