Nod2 Deficiency in mice is Associated with Microbiota Variation Favouring the Expansion of mucosal CD4+ LAP+ Regulatory Cells

Nucleotide-binding Oligomerization Domain-2 (NOD2) mutations are associated with an increased risk to develop Crohn's Disease. In previous studies, we have shown that Nod2-/- mice manifest increased proportion of Lamina Propria (LP) CD4+ LAP+ Foxp3- regulatory cells, when compared with Nod2+/+ mice, while CD4+ Foxp3 + regulatory cells were not affected. Here, we investigated the Nod2 gut microbiota, by 16S rRNA pyrosequencing, at steady state and after TNBS-colitis induction in mice reared separately or in cohousing, correlating the microbial profiles with LP regulatory T cells proportion and tissue cytokines content. We found that enrichment of Rikenella and Alistipes (Rikenellaceae) in Nod2-/- mice at 8 weeks of age reared separately was associated with increased proportion of CD4+ LAP+ Foxp3- cells and less severe TNBS-colitis. In co-housed mice the acquisition of Rickenellaceae by Nod2+/+ mice was associated with increased CD4+ LAP+ Foxp3- proportion and less severe colitis. Severe colitis was associated with enrichment of gram-negative pathobionts (Escherichia and Enterococcus), while less severe colitis with protective bacteria (Barnesiella, Odoribacter and Clostridium IV). Environmental factors acting on genetic background with different outcomes according to their impact on microbiota, predispose in different ways to inflammation. These results open a new scenario for therapeutic attempt to re-establish eubiosis in Inflammatory Bowel Disease patients with NOD2 polymorphisms

Influence of the medium length on high-order harmonic generation

We study high-order harmonic generation using a 110 fs Ti:sapphire laser loosely focused into a variable-length gas cell filled with neon or argon at 5 mbar pressure. The harmonic intensity is recorded as a function of the medium length, varying between 2 and 21 mm. Several cases are examined, the 17th and the 29th harmonic in argon, and the 29th and 51st harmonic in neon, at the same intensity 4 x 10(14) W cm(-2). We find that the length which maximizes the harmonic yield varies from 10 mm to more than 20 mm. We discuss the different effects affecting the photon yield of the high-order harmonics

A pilot study of the role of corn dextrin and milk peptides supplementation on faecal microbiota in healthy adults

The gastrointestinal microbiota has an important role in human health. Dietary interventions are of great interest to modulate the composition and metabolic functions of the gut microbial communities and to improve health, and prevent or treat diseases. Consumption of prebiotics is one dietary strategy for beneficial manipulation of the gut microbiota, because it allows increasing the fibre intake, especially in people with western dietary habits, who do not take the recommended daily amount of fiber. Interestingly, milk peptides can also positively affect the beneficial gut microorganisms. The present work is a pilot study aimed to investigate the effect of a prebiotic supplementation on composition and metabolic activity of microorganisms living in the human gut. In this trial, 12 healthy subjects received 10g/die of supplement Biotransit\uae, composed by corn derived dextrin and milk peptides, produced and marketed in Italy by Depofarma (Italy), for 4 weeks with a 2 weeks washout. Outcome measures were assessed at four time points (before the supplementation T0-1, T0-2, at the end of intervention, T30 and after washout, T45), including gut microbiota profiling by 16S rRNA gene sequencing and intestinal functional metabolism measuring faecal Short Chain Fatty Acid concentrations (SCFAs). The effects of the Biotransit supplementation on bifidobacteria were also assessed with culture dependent techniques. Gut microbiota analysis revealed that Biotransit\uae supplementation after 30 days did not exert effects on the overall gut microbiota structure. Although no significant differences on alpha diversity were obtained, we observed an increase of diversity after 30 days of treatment. Beta diversity analysis, calculated on Bray-Curtis distances revealed significant differences comparing T0 vs T45 and T30 vs T45. Interestingly, at T45, we found an enrichment of Porphyromonadaceae. Biotransit\uae induced quantitative changes in cultivable bifidobacteria with increased amount at T45, even if the total number of species has not been influenced. Biotransit\uae supplementation is also associated to an increase total SCFAs concentration in T30 and T45, in particular related to acetate, propionate and butyrate (p < 0.05). Future study will be aimed to follow the time course of the persistence of this effect after the end of treatment

Dipolar degrees of freedom and Isospin equilibration processes in Heavy Ion collisions

Background: In heavy ion collision at the Fermi energies Isospin equilibration processes occur- ring when nuclei with different charge/mass asymmetries interacts have been investigated to get information on the nucleon-nucleon Iso-vectorial effective interaction. Purpose: In this paper, for the system 48Ca +27 Al at 40 MeV/nucleon, we investigate on this process by means of an observable tightly linked to isospin equilibration processes and sensitive in exclusive way to the dynamical stage of the collision. From the comparison with dynamical model calculations we want also to obtain information on the Iso-vectorial effective microscopic interaction. Method: The average time derivative of the total dipole associated to the relative motion of all emitted charged particles and fragments has been determined from the measured charges and velocities by using the 4? multi-detector CHIMERA. The average has been determined for semi- peripheral collisions and for different charges Zb of the biggest produced fragment. Experimental evidences collected for the systems 27Al+48Ca and 27Al+40Ca at 40 MeV/nucleon used to support this novel method of investigation are also discussed.Comment: Submitted for publication on Phys. Rev. C. 0n 24-oct-201

Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association

The application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood

Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and Rural Africa

peer reviewe

Altered gut microbiota in Rett syndrome

Background The human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Rett syndrome (RTT), a progressive neurological disorder mainly caused by mutations in MeCP2 gene, is commonly associated with gastrointestinal dysfunctions and constipation, suggesting a link between RTT’s gastrointestinal abnormalities and the gut microbiota. The aim of this study was to evaluate the bacterial and fungal gut microbiota in a cohort of RTT subjects integrating clinical, metabolomics and metagenomics data to understand if changes in the gut microbiota of RTT subjects could be associated with gastrointestinal abnormalities and inflammatory status. Results Our findings revealed the occurrence of an intestinal sub-inflammatory status in RTT subjects as measured by the elevated values of faecal calprotectin and erythrocyte sedimentation rate. We showed that, overall, RTT subjects harbour bacterial and fungal microbiota altered in terms of relative abundances from those of healthy controls, with a reduced microbial richness and dominated by microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida. We further observed that alterations of the gut microbiota do not depend on the constipation status of RTT subjects and that this dysbiotic microbiota produced altered short chain fatty acids profiles. Conclusions We demonstrated for the first time that RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that impairments of MeCP2 functioning favour the establishment of a microbial community adapted to the costive gastrointestinal niche of RTT subjects. The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT subjects and contribute to RTT gastrointestinal physiopathology

Treatment of atrial fibrillation with a dual defibrillator in heart failure patients (TRADE HF): protocol for a randomized clinical trial.

Background: Heart failure(HF) and atrial fibrillation(AF) frequently coexist in the same patient and are associated with increased mortality and frequent hospitalizations. As the concomitance of AF and HF is often associated with a poor prognosis, the prompt treatment of AF in HF patients may significantly improve outcome.Methods/design: Recent implantable cardiac resynchronization (CRT) devices allow electrical therapies to treat AF automatically. TRADE-HF (trial registration: NCT00345592; http://www.clinicaltrials.gov) is a prospective, randomized, double arm study aimed at demonstrating the efficacy of an automatic, device-based therapy for treatment of atrial tachycardia and fibrillation(AT/AF) in patients indicated for CRT. The study compares automatic electrical therapy to a traditional more usual treatment of AT/AF: the goal is to demonstrate a reduction in a combined endpoint of unplanned hospitalizations for cardiac reasons, death from cardiovascular causes or permanent AF when using automatic atrial therapy as compared to the traditional approach involving hospitalization for symptoms and in-hospital treatment of AT/AF.Discussion: CRT pacemaker with the additional ability to convert AF as well as ventricular arrhythmias may play a simultaneous role in rhythm control and HF treatment. The value of the systematic implantation of CRT ICDs with the capacity to deliver atrial therapy in HF patients at risk of AF has not yet been explored. The TRADE-HF study will assess in CRT patients whether a strategy based on automatic management of atrial arrhythmias might be a valuable option to reduce the number of hospital admission and to reduce the progression the arrhythmia to a permanent for