The Role of Gut Microbiota Biomodulators on Mucosal Immunity and Intestinal Inflammation

Alterations of the gut microbiota may cause dysregulated mucosal immune responses leading to the onset of inflammatory bowel diseases (IBD) in genetically susceptible hosts. Restoring immune homeostasis through the normalization of the gut microbiota is now considered a valuable therapeutic approach to treat IBD patients. The customization of microbe-targeted therapies, including antibiotics, prebiotics, live biotherapeutics and faecal microbiota transplantation, is therefore considered to support current therapies in IBD management. In this review, we will discuss recent advancements in the understanding of host-microbe interactions in IBD and the basis to promote homeostatic immune responses through microbe-targeted therapies. By considering gut microbiota dysbiosis as a key feature for the establishment of chronic inflammatory events, in the near future it will be suitable to design new cost-effective, physiologic, and patient-oriented therapeutic strategies for the treatment of IBD that can be applied in a personalized manner

Effect of layered double hydroxide intercalated with fluoride ions on the physical, biological and release properties of a dental composite resin

OBJECTIVES: The aim of this work was the preparation of a new fluoride-releasing dental material characterized by a release of fluoride relatively constant over time without any initial toxic burst effect. This type of delivery is obtained by a matrix controlled elution and elicits the beneficial effect of a low amount of fluoride on human dental pulp stem cells (hDPSCs) towards mature phenotype. METHODS: The modified hydrotalcite intercalated with fluoride ions (LDH-F), used as filler, was prepared via ion exchange procedure and characterized by X-ray diffraction and FT-IR spectroscopy. The LDH-F inorganic particles (0.7, 5, 10, 20wt.%) were mixed with a photo-activated Bis-GMA/TEGDMA (45/55wt/wt) matrix and novel visible-light cured composites were prepared. The dynamic thermo-mechanical properties were determined by dynamic mechanical analyzer. The release of fluoride ions in physiological solution was determined using a ionometer. Total DNA content was measured by a PicoGreen dsDNA quantification kit to assess the proliferation rate of hDPSCs. Alkaline phosphatase activity (ALP) was measured in presence of fluoride resins. RESULTS: Incorporation of even small mass fractions (e.g. 0.7 and 5wt.%) of the fluoride LDH in Bis-GMA/TEGDMA dental resin significantly improved the mechanical properties of the pristine resin, in particular at 37°C. The observed reinforcement increases on increasing the filler concentration. The release of fluoride ions resulted very slow, lasting months. ALP activity gradually increased for 28 days in hDPSCs cell grown, demonstrating that low concentrations of fluoride contributed to the cell differentiation. CONCLUSIONS: The prepared composites containing different amount of hydrotalcite filler showed improved mechanical properties, slow fluoride release and promoted hDPSCs cell proliferation and cell differentiation

Neuroradiological findings in Alagille syndrome

Alagille syndrome (ALGS) is a multisystemic disease caused by mutations in genes of Notch pathway, which regulates embryonic cell differentiation and angiogenesis. Clinically, ALGS is characterized by cholestasis, cardiac defects, characteristic facial features, skeletal and ophthalmologic abnormalities. The aim of this review is to illustrate neuroradiological findings in ALGS, which are less well-known and prevalent, including cerebrovascular anomalies (such as aneurysms, dolichoectasia, Moyamoya syndrome and venous peculiarities), Chiari 1 malformation, craniosynostosis, intracranial hypertension, and vertebral anomalies (namely butterfly vertebra, hemivertebra, and craniocervical junction anomalies). Rarer cerebral midline malformations and temporal bone anomalies have also been described

NOSTROMO - D1.2 - Final Project Results Report

The main objective of the NOSTROMO project has been to develop, demonstrate and evaluate an innovative modelling approach for the rigorous and comprehensive assessment of the performance impact of future ATM concepts and solutions at ECAC network level. This approach brings together the ability of bottom-up microscopic models to capture emergent behaviour and interdependencies between different solutions with the level of tractability and interpretability required to effectively support decision-making. This report provides a summary of NOSTROMO accomplishments and contributions to the SESAR Programme. It gathers technical lessons learned and concludes proposing further developments to facilitate the use of the NOSTROMO methodology in the future SESAR 3 Programme

Impedance measurements and simulations on the TCT and TDI LHC collimators

The LHC collimation system is a critical element for the safe operation of the LHC machine and it is subject to continuous performance monitoring, hardware upgrade and optimization. In this work we will address the impact on impedance of the upgrades performed on the injection protection target dump (TDI), where the absorber material has been changed to mitigate the device heating observed in machine operation, and on selected secondary (TCS) and tertiary (TCT) collimators, where beam position monitors (BPM) have been embedded for faster jaw alignment. Con- cerning the TDI, we will present the RF measurements per- formed before and after the upgrade, comparing the result to heating and tune shift beam measurements. For the TCTs, we will study how the higher order modes (HOM) intro- duced by the BPM addition have been cured by means of ferrite placement in the device. The impedance mitigation campaign has been supported by RF measurements whose results are in good agreement with GdfidL and CST simula- tions. The presence of undamped low frequency modes is proved not to be detrimental to the safe LHC operation

In vitro elicitation of intestinal immune Responses in Teleost Fish: evidence for a type IV hypersensitivity reaction in Rainbow Trout.

In fish the gut immune system has been the subject of few investigations until now. Here, we provide novel morphological and immunological data on the gut isolated from rainbow trout Salmo gairdneri. The pyloric (P) and terminal (T) segments of trout gut, when morphologically examined, evidenced lymphocytes and macrophages (MO) loosely dispersed in the intestinal mucosa and in the lamina propria in the absence of typical Peyer's patches-like structures. Furthermore, incubation of P and T sections with Candida albicans (Ca) and functional analysis of supernatants generated some interesting results. In fact, active supernatants, when compared with controls, exhibited cytokine-like activities attributable to the presence of interferon (IFN)-gamma and migration inhibiting factor (MIF), respectively. In particular, IFN-gamma-like activity gave rise to an enhancement of Ca phagocytosis by MO, whereas MIF inhibited MO migration in agarose. Taken together, these in vitro data suggest that the gut-associated lymphoreticular tissue in fish possesses the appropriate armamentarium to mount a type IV hypersensitivity response when challenged by microbial antigens

Auger radiation targeted into DNA: a therapy perspective

BACKGROUND: Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of alpha particles. In contrast to alpha radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies. DISCUSSION: Here, we will discuss the basic principles of Auger electron therapy as compared with vector-guided alpha and beta radiation. We also review some radioprotection issues and briefly present the main advantages and disadvantages of the different targeting modalities that are under investigation

Mechanism of retinoic acid-induced transcription: histone code, DNA oxidation and formation of chromatin loops

Histone methylation changes and formation of chro- matin loops involving enhancers, promoters and 3′ end regions of genes have been variously associ- ated with active transcription in eukaryotes. We have studied the effect of activation of the retinoic A re- ceptor, at the RARE–promoter chromatin of CASP9 and CYP26A1 genes, 15 and 45 min following RA ex- posure, and we found that histone H3 lysines 4 and 9 are demethylated by the lysine-specific demethylase, LSD1 and by the JMJ-domain containing demethy- lase, D2A. The action of the oxidase (LSD1) and a dioxygenase (JMJD2A) in the presence of Fe++ elic- its an oxidation wave that locally modifies the DNA and recruits the enzymes involved in base and nu- cleotide excision repair (BER and NER). These events are essential for the formation of chromatin loop(s) that juxtapose the RARE element with the 5′ tran- scription start site and the 3′ end of the genes. The RARE bound-receptor governs the 5′ and 3′ end se- lection and directs the productive transcription cycle of RNA polymerase. These data mechanistically link chromatin loops, histone methylation changes and localized DNA repair with transcription

Short fluorodeoxyuridine exposure of different human glioblastoma lines induces high-level accumulation of S-phase cells that avidly incorporate 125I-iododeoxyuridine.

PURPOSE: Radio-iododeoxyuridine (IdUrd) is a potential Auger radiation therapy agent incorporated into DNA during the synthesis phase. In this study we sought to optimise S-phase targeting by modulating cellular cycling and radio-IdUrd DNA incorporation using short non-toxic fluorodeoxyuridine (FdUrd) incubations. METHODS: Three human glioblastoma cell lines with different p53 expression were pre-treated with various FdUrd conditions. After different intervals, (125)I-IdUrd DNA incorporation was measured. Fluorescence-activated cell sorter cell cycle analysis was performed after identical intervals post FdUrd pre-treatment. RESULTS: The highest increase in (125)I-IdUrd DNA incorporation was induced by 1-h incubation with 1 muM FdUrd. Increase in radio-IdUrd DNA incorporation was greatest 16-24 h after FdUrd, reaching factors of >or=7.5 over baseline incorporation in the three cell lines. Furthermore, cell synchronisation in S phase was observed with a peak of >or=69.5% in the three cell lines at 16 and 24 h post FdUrd, corresponding to an increase of 2.5-4.1 over baseline. CONCLUSION: FdUrd-induced thymidine synthesis inhibition led to S-phase accumulation that was maximal after an interval of 16-24 h and time-correlated with the highest radio-IdUrd DNA incorporation. These observations might allow the rational design of an Auger radiation therapy targeting a maximal number of S-phase cells in single treatment cycles