Mitochondrial dysfunction generates aggregates that resist lysosomal degradation in human breast cancer cells

Disrupting functional protein homeostasis is an established therapeutic strategy for certain tumors. Ongoing studies are evaluating autophagy inhibition for overcoming chemotherapeutic resistance to such therapies by neutralizing lysosomal pH. New and sensitive methods to monitor autophagy in patients are needed to improve trial design and interpretation. We report that mitochondrial-damaged breast cancer cells and rat breast tumors accumulate p53-positive protein aggregates that resist lysosomal degradation. These aggregates were localized to enzymatically-active autolysosomes that were degrading autophagosomes and the autophagic receptor proteins TAX1BP1 and NDP52. NDP52 was identified to associate with aggregated proteins and knocking down NDP52 led to the accumulation of protein aggregates. TAX1BP1 was identified to partly localize with aggregates, and knocking down TAX1BP1 enhanced aggregate formation, suppressed autophagy, impaired NDP52 autophagic degradation and induced cell death. We propose that quantifying aggregates and autophagic receptors are two potential methods to evaluate autophagy and lysosomal degradation, as confirmed using primary human tumor samples. Collectively, this report establishes protein aggregates and autophagy receptors, TAX1BP1 and NDP52, as potential endpoints for monitoring autophagy during drug development and clinical studies

Chemo- and Thermosensory Responsiveness of Grueneberg Ganglion Neurons Relies on Cyclic Guanosine Monophosphate Signaling Elements

Neurons of the Grueneberg ganglion (GG) in the anterior nasal region of mouse pups respond to cool temperatures and to a small set of odorants. While the thermosensory reactivity appears to be mediated by elements of a cyclic guanosine monophosphate (cGMP) cascade, the molecular mechanisms underlying the odor-induced responses are unclear. Since odor-responsive GG cells are endowed with elements of a cGMP pathway, specifically the transmembrane guanylyl cyclase subtype GC-G and the cyclic nucleotide-gated ion channel CNGA3, the possibility was explored whether these cGMP signaling elements may also be involved in chemosensory GG responses. Experiments with transgenic mice deficient for GC-G or CNGA3 revealed that GG responsiveness to given odorants was significantly diminished in these knockout animals. These findings suggest that a cGMP cascade may be important for both olfactory and thermosensory signaling in the GG. However, in contrast to the thermosensory reactivity, which did not decline over time, the chemosensory response underwent adaptation upon extended stimulation, suggesting that the two transduction processes only partially overlap. Copyright (C) 2011 S. Karger AG, Base

Adsorbate and defect effects on electronic and transport properties of gold nanotubes

First-principles calculations have been performed to study the effects of adsorbates (CO molecules and O atoms) and defects on electronic structures and transport properties of Au nanotubes (Au(5, 3) and Au(5, 5)). For CO adsorption, various adsorption sites of CO on the Au tubes were considered. The vibrational frequency of the CO molecule was found to be very different for two nearly degenerate stable adsorption configurations of Au(5, 3), implying the possibility of distinguishing these two configurations via measuring the vibrational frequency of CO in experiments. After CO adsorption, the conductance of Au(5, 3) decreases by 0.9G0 and the conductance of Au(5, 5) decreases by approximately 0.5G0. For O-adsorbed Au tubes, O atoms strongly interact with Au tubes, leading to around 2G0 of drop in conductance for both Au tubes. These results may have implications for Au-tube-based chemical sensing. When a monovacancy defect is present, we found that, for both tubes, the conductance decreases by around 1G0. Another type of defect arising from the adhesion of one Au atom is also considered. For this case, it is found that, for the Au(5, 3) tube, the defect decreases the conductance by nearly 1G0, whereas for Au(5, 5), the decrease in conductance is only 0.3G0.Comment: 7 pages, 8 figure

Growth factors of stem cell niche extend the life-span of precision-cut intestinal slices in culture:A proof-of-concept study

Precision-cut intestinal slices (PCIS) is an ex vivo culture technique that found its applications in toxicology, drug transport and drug metabolism testing, as well as in fibrosis research. The main limiting factor of PCIS as experimental model is the relatively short viability of tissue slices. Here, we describe a strategy for extending the life-span of PCIS during culture using medium that is routinely used for growing intestinal organoids. Mouse and rat PCIS cultured in standard medium progressively showed low ATP/protein content and severe tissue degradation, indicating loss of tissue viability. In turn, organoid medium, containing epithelial growth factor (EGF), Noggin and R-spondin, maintained significantly higher ATP/protein levels and better preserved intestinal architecture of mouse PCIS at 96 h. In contrast, organoid medium that additionally contained Wnt, had a clear positive effect on the ATP content of rat PCIS during 24 h of culture, but not on slice histomorphology. Our proof-of-concept study provides early evidence that employing organoid medium for PCIS culture improved tissue viability during extended incubation. Enabling lasting PCIS cultures will greatly widen their range of applications in predicting long-term intestinal toxicity of xenobiotics and elucidating their mechanism of action, among others

Ab initio study of transport properties in defected carbon nanotubes: an O(N) approach

A combination of ab initio simulations and linear-scaling Green's functions techniques is used to analyze the transport properties of long (up to one micron) carbon nanotubes with realistic disorder. The energetics and the influence of single defects (mono- and di-vacancies) on the electronic and transport properties of single-walled armchair carbon nanotubes are analyzed as a function of the tube diameter by means of the local orbital first-principles Fireball code. Efficient O(N) Green's functions techniques framed within the Landauer-Buttiker formalism allow a statistical study of the nanotube conductance averaged over a large sample of defected tubes and thus extraction of the nanotubes localization length. Both the cases of zero and room temperature are addressed.Comment: 15 pages, 12 figures (submitted to J. Phys: Condens. Matter

Social Preferences, Skill Segregation and Wage Dynamics

We study the earning structure and the equilibrium asignment of workers to firms in a model in which workers have social preferences, and skills are perfectly substitutable in production. Firms offer long-term contracts, and we allow for frictions in the labour market in the form of mobility costs. The model delivers specific predictions about the nature of worker flows, about the characteristic of workplace skill segregation, and about wage dispersion both within and cross firms. We shows that long-term contracts in the resence of social preferences associate within-firm wage dispersion with novel "internal labour market" features such as gradual promotions, productivity-unrelated wage increases, and downward wage flexibility. These three dynamic features lead to productivity-unrelated wage volatily within firms.Publicad

Acidification and solar drying of manure-based digestate to produce improved fertilizing products

The increase in energy and fertilizer consumption makes it necessary to develop sustainable alternatives for agriculture. Anaerobic digestion and digestates appeared to be suitable options. However, untreated digestates still have high water content and can increase greenhouse gas emissions during storage and land application. In this study, manure-derived digestate and solid fraction of digestate after separation were treated with a novel solar drying technology to reduce their water content, combined with acidification to reduce the gaseous emissions. The acidified digestate and acidified solid fraction of digestate recovered more nitrogen and ammonia nitrogen than their respective non-acidified products (1.5–1.3 times for TN; 14 times for TAN). Ammonia and methane emissions were reduced up to 94% and 72% respectively, compared to the non-acidified ones, while N2O increased more than 3 times. Dried digestate and dried acidified digestate can be labeled as NPK organic fertilizer regarding the European regulation, and the dried solid fraction and the improved dried acidified solid fraction can be labeled as N or P organic fertilizer. Moreover, plant tests showed that N concentrations in fresh lettuce leaves were within the EU limit with all products in all the cases. However, zinc concentration appeared to be a limitation in some of the products as their concentration exceeded the European legal limits.This work was funded by the European Union under the Circular Agronomics project (H2020 research and innovation project Nº.773649) and Nutry2Cycle project (H2020 research and innovation project Nº.773682). IRTA thanks the support of the CERCA Program and the Consolidated Research Group TERRA (ref.2017SGR1292), both from the Generalitat de Catalunya. L. Morey thanks the financial support of AGAUR, of the Generalitat de Catalunya (grant reference number 2019FI_B00694). We would like to thank the help of Celia Segura Godoy and Pau Berenguer i Planas during the sampling campaigns.Peer ReviewedPostprint (published version