LPS-induced IL-8 activation in human intestinal epithelial cells is accompanied by specific histone H3 acetylation and methylation changes

<p>Abstract</p> <p>Background</p> <p>The release of LPS by bacteria stimulates both immune and specific epithelial cell types to release inflammatory mediators. It is known that LPS induces the release of IL-8 by intestinal mucosal cells. Because it is now emerging that bacteria may induce alteration of epigenetic patterns in host cells, we have investigated whether LPS-induced IL-8 activation in human intestinal epithelial cells involves changes of histone modifications and/or DNA methylation at IL-8 gene regulatory region.</p> <p>Results</p> <p>RT-PCR analysis showed that IL-8 mRNA levels rapidly increase after exposure of HT-29 cells to LPS. DNA demethylating agents had no effects on IL-8 expression, suggesting that DNA methylation was not involved in IL-8 gene regulation. Consistently we found that 5 CpG sites located around IL-8 transcription start site (-83, -7, +73, +119, +191) were unmethylated on both lower and upper strand either in LPS treated or in untreated HT-29 cells, as well as in normal intestinal mucosa.</p> <p>Conversely, pretreatment of HT-29 cells with deacetylase inhibitors strengthened the LPS-mediated IL-8 activation. Inhibitors of histone deacetylases could induce IL-8 mRNA expression also in the absence of LPS, suggesting that chromatin modifications could be involved in IL-8 gene regulation. Chromatin immunoprecipitation analyses showed that, concurrently with IL-8 activation, transient specific changes in H3 acetylation and H3K4, H3K9 and H3K27 methylation occurred at IL-8 gene promoter during LPS stimulation. Changes of H3-acetyl, H3K4me2 and H3K9me2 levels occurred early, transiently and corresponded to transcriptional activity, while changes of H3K27me3 levels at IL-8 gene occurred later and were long lasting.</p> <p>Conclusion</p> <p>The results showed that specific chromatin modifications occurring at IL-8 gene, including histone H3 acetylation and methylation, mark LPS-mediated IL-8 activation in intestinal epithelial cells while it is unlikely that DNA methylation of IL-8 promoter is directly involved in IL-8 gene regulation in these cells.</p

An Unsupervised Spectrogram Cross-Correlation Method to Assess ELM Triggering Efficiency by Pellets

The high confinement mode (H-mode) is considered the optimal regime for the production of energy through nuclear fusion for industrial purposes since it allows to increase the energy confinement time of the plasma roughly by a factor of two. Consequently, it has been selected at the moment as the standard scenario for the next generation of devices, such as ITER. However, pressure-driven edge instabilities, known as edge localized modes (ELMs), are a distinct feature of this plasma regime. Their extrapolated thermal and particle peak loads on the plasma-facing components (PFC) of the next generation of devices are expected to be so high as to damage such structures, compromising the normal operations of the reactors themselves. Consequently, the induced loads have to be controlled; this can be achieved by mitigating ELMs. A possibility then lays in increasing the ELMs frequency to lower the loads on the PFCs. As already demonstrated at JET, the pellet pacing of ELMs is considered one of the most promising techniques for such scope, and its optimization is therefore of great interest for present and future operations of nuclear fusion facilities. In this work, we suggest a method to access primary pieces of information to perform statistics, assess and characterize the pacing efficiency. The method, tested on JET data, is based on the clustering (k-means) of convoluted signals, using so-called spectrogram cross-correlation, between the measured pellets and ELMs time traces. Results have also been obtained by taking advantage of a new type of diagnostic for measuring the ELMs dynamic, based on synthetic diamond sensors, faster than the standard spectroscopic cameras used at JET

Analysis third age university and open one about physical activities and sports sciences

Practical activities play an important role in many training fields. In a previous analysis the role of these activities in the universities of the third age has been seen and how this plays a marginal role. In this paper, the role of motor practice in remote or telematic universities will be verified and evaluated through a qualitative analysis. Despite being created with the aim of facilitating the most isolated people, these have advantages and disadvantages. The pros and cons of the third age third age universities and all the classes of competition regarding the practice of sport will be analysed in a comparative way: L-22 Sciences of physical and sports activities, LM 47 organization and management of services for sport and for motor activities, LM 67 Sciences and techniques of preventive and adapted motor activities, LM 68 Sports sciences and techniques. The aim of the research is to provide a critical evaluation concerning the methods of administration of the sports practice and the training activities of these university structures. The results lead to the conclusion that in telematic universities the activities are not adequate for the purpose since in these structures the activities at a practical level are almost completely non-existent; while about the internship activities, if present, it takes place in affiliated facilities without any direct control of the university to which they belong. Since the universities must guarantee a training path adapted to the needs of the students, they must promote an educational plan that is as close as possible to that of the traditional universities

VirusMINT: a viral protein interaction database

Understanding the consequences on host physiology induced by viral infection requires complete understanding of the perturbations caused by virus proteins on the cellular protein interaction network. The VirusMINT database (http://mint.bio.uniroma2.it/virusmint/) aims at collecting all protein interactions between viral and human proteins reported in the literature. VirusMINT currently stores over 5000 interactions involving more than 490 unique viral proteins from more than 110 different viral strains. The whole data set can be easily queried through the search pages and the results can be displayed with a graphical viewer. The curation effort has focused on manuscripts reporting interactions between human proteins and proteins encoded by some of the most medically relevant viruses: papilloma viruses, human immunodeficiency virus 1, Epstein–Barr virus, hepatitis B virus, hepatitis C virus, herpes viruses and Simian virus 40

Targeting Taxanes to Castration-Resistant Prostate Cancer Cells by Nanobubbles and Extracorporeal Shock Waves

To target taxanes to castration-resistant prostate cancer cells, glycol-chitosan nanobubbles loaded with paclitaxel and docetaxel were constructed. The loaded nanobubbles were then combined with Extracorporeal Shock Waves, acoustic waves widely used in urology and orthopedics, with no side effects. Nanobubbles, with an average diameter of 353.3 ± 15.5 nm, entered two different castration-resistant prostate cancer cells (PC3 and DU145) as demonstrated by flow cytometry and immunofluorescence. The shock waves applied increased the amount of intracellular nanobubbles. Loading nanobubbles with paclitaxel and docetaxel and combining them with shock waves generated the highest cytotoxic effects, resulting in a paclitaxel GI50 reduction of about 55% and in a docetaxel GI50 reduction of about 45% respectively. Combined treatment also affected cell migration. Paclitaxel-loaded nanobubbles and shock waves reduced cell migration by more than 85% with respect to paclitaxel alone; whereas docetaxel-loaded nanobubbles and shock waves reduced cell migration by more than 82% with respect to docetaxel alone. The present data suggest that nanobubbles can act as a stable taxane reservoir in castration-resistant prostate cancer cells and shock waves can further increase drug release from nanobubbles leading to higher cytotoxic and anti-migration effect

The Discovery of Highly Potent THP Derivatives as OCTN2 Inhibitors: From Structure‐Based Virtual Screening to In Vivo Biological Activity

A mismatch between β‐oxidation and the tricarboxylic acid cycle (TCA) cycle flux in mitochondria produces an accumulation of lipid metabolic intermediates, resulting in both blunted metabolic flexibility and decreased glucose utilization in the affected cells. The ability of the cell to switch to glucose as an energy substrate can be restored by reducing the reliance of the cell on fatty acid oxidation. The inhibition of the carnitine system, limiting the carnitine shuttle to the oxidation of lipids in the mitochondria, allows cells to develop a high plasticity to metabolic rewiring with a decrease in fatty acid oxidation and a parallel increase in glucose oxidation. We found that 3‐(2,2,2‐ trimethylhydrazine)propionate (THP), which is able to reduce cellular carnitine levels by blocking both carnitine biosynthesis and the cell membrane carnitine/organic cation transporter (OCTN2), was reported to improve mitochondrial dysfunction in several diseases, such as Huntington’s disease (HD). Here, new THP‐derived carnitine‐lowering agents (TCL), characterized by a high affinity for the OCTN2 with a minimal effect on carnitine synthesis, were developed, and their biological activities were evaluated in both in vitro and in vivo HD models. Certain compounds showed promising biological activities: reducing protein aggregates in HD cells, ameliorating motility defects, and increasing the lifespan of HD Drosophila melanogaster

Psychophysical benefits of recreational five-a-side football

Nowadays, recreational sports activities are focused on health and wellness aspects for a physiological study on the effects of the elite sport due to the spread of recreational sport, especially football. This work addresses the physical benefits originated from recreational five-a-side football and aims at the perceptions about self-evaluation of the physical and the psychological data. It also proposes a questionnaire in a group of young men aged 23 to 29 who played amateur five-a-side football for 8 weeks just 2-3 times a week. The requests basing on the overall research conclusions on the studies performed on recreational football (Kustrup et al., 2010). The most significant results showed that practicing amateur sports activities makes you feel better both physically and psychologically (respectively 87,3% e 93,3% of the answers) and it is less tiring and stressful than playing football agonistically (respectively 80% e 80% of the answers) or practicing strength training or interval running training. Furthermore, according to the data complex, it can be potentially satisfactory from the point of the view healthy and well-ness sport that can improve general well-being and it can prevent lethal diseases, such as cardiovascular diseases and obesity. In conclusion, it can be affirmed that recreational five-a-side football can produce not only physical benefits, as Kustrup's article shows, but also significant psychological benefits, which makes you feel better and more relaxed

Multimodal lung cancer screening using the ITALUNG Biomarker Panel and Low Dose Computed Tomography. Results of the ITALUNG biomarker study

Asymptomatic high-risk subjects, randomized in the intervention arm of the ITALUNG trial (1406 screened for lung cancer), were enrolled for the ITALUNG biomarker study (n = 1356), in which samples of blood and sputum were analysed for plasma DNA quantification (cut off 5ng/ml), loss of heterozygosity and microsatellite instability. The ITALUNG biomarker panel (IBP) was considered positive if at least one of the two biomarkers included in the panel was positive. Subjects with and without lung cancer diagnosis at the end of the screening cycle with LDCT (n = 517) were evaluated. Out of 18 baseline screen detected lung cancer cases, 17 were IBP positive (94%). Repeat screen-detected lung cancer cases were 18 and 12 of them positive at baseline IBP test (66%). Interval cancer cases (2-years) and biomarker tests after a suspect Non Calcific Nodule follow-up were investigated. The single test versus multimodal screening measures of accuracy were compared in a simulation within the screened ITALUNG intervention arm, considering screen-detected and interval cancer cases. Sensitivity was 90% at baseline screening. Specificity was 71%% and 61% for LDCT and IBP as baseline single test, and improved at 89% with multimodal, combined screening. The positive predictive value was 4.3% for LDCT at baseline and 10.6% for multimodal screening. Multimodal screening could improve the screening efficiency at baseline and strategies for future implementation are discussed. If IBP was used as primary screening test, the LDCT burden might decrease of about 60%

Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3

: Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi-allelic variants in one of the genes involved in the Notch signaling pathway that tunes the "segmentation clock" of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio-based exome sequencing (trio-ES) to carry homozygous (c.822-5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822-5C>T change, affecting the polypyrimidine tract of intron 5, is the first non-coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio-ES approach in prenatal and neonatal settings