The noradrenergic component in tapentadol action counteracts \u3bc-opioid receptor-mediated adverse effects on adult neurogenesis

Opiates were the first drugs shown to negatively impact neurogenesis in the adult mammalian hippocampus. Literature data also suggest that norepinephrine is a positive modulator of hippocampal neurogenesis in vitro and in vivo. On the basis of these observations, we investigated whether tapentadol, a novel central analgesic combining \u3bc-opioid receptor (MOR) agonism with norepinephrine reuptake inhibition (NRI), may produce less inhibition of hippocampal neurogenesis compared with morphine. When tested in vitro, morphine inhibited neuronal differentiation, neurite outgrowth, and survival of adult mouse hippocampal neural progenitors and their progeny, via MOR interaction. By contrast, tapentadol was devoid of these adverse effects on cell survival and reduced neurite outgrowth and the number of newly generated neurons only at nanomolar concentrations where the MOR component is predominant. On the contrary, at higher (micromolar) concentrations, tapentadol elicited proneurogenic and antiapoptotic effects via activation of \u3b22 and \u3b12 adrenergic receptors, respectively. Altogether, these data suggest that the noradrenergic component in tapentadol has the potential to counteract the adverse MOR-mediated effects on hippocampal neurogenesis. As a proof of concept, we showed that reboxetine, an NRI antidepressant, counteracted both antineurogenic and apoptotic effects of morphine in vitro. In line with these observations, chronic tapentadol treatment did not negatively affect hippocampal neurogenesis in vivo. In light of the increasing long-term use of opiates in chronic pain, in principle, the tapentadol combined mechanism of action may result in less or no reduction in adult neurogenesis compared with classic opiates

A spasso per Recanati, Citt\ue0 della poesia. Guida per ragazzi e ragazze

Una guida turistica alla citt\ue0 di Recanati pensata per i pi\uf9 piccol

\u201cA spasso con un leone nel paese dei\u2026 Leopardi"

Creare un'app interattiva che permetta la visita guidata ai luoghi leopardiani, legata in particolare al turismo scolastic

A proposito di classi 2.0: analisi dei risultati di un'esperienza

The aim of the research was to understand the impact of using tablet in school environment, both on learning results and on indirect psycho-social variables such as motivation, self representation, group dynamics, and use of new technologies in extra-scholastic contexts. We monitored the above variables in two classes of 11 to 12 years old students. The experimental class was provided of tablets and the control class attended a traditional path. We planned two online data collections through questionnaires at the beginning, and at the end of the scholastic year. At the second survey, in comparison with the control class, the students of the experimental class showed a greater motivation to learn, a larger positive development in their self representations, a deeper and more complex dynamics of peer's interaction within the class, and a frequent use of new technologies in extra-scholastic contexts

Gut Microbiota and Associated Mucosal Immune Response in Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A genome-wide association study showed a correlation between ANCA-negative EGPA and variants of genes encoding proteins with intestinal barrier functions, suggesting that modifications of the mucosal layer and consequent gut dysbiosis might be involved in EGPA pathogenesis. Here, we characterized the gut microbiota (GM) composition and the intestinal immune response in a cohort of EGPA patients. Faeces from 29 patients and 9 unrelated healthy cohabitants were collected, and GM and derived metabolites’ composition were compared. Seven intestinal biopsies from EGPA patients with gastrointestinal manifestations were analysed to assess the T-cell distribution and its correlation with GM and EGPA clinical and laboratory features. No significant differences in GM composition, nor in the total amount of faecal metabolites, emerged between patients and controls. Nevertheless, differences in bacterial taxa abundances and compositional GM-derived metabolites profile were observed. Notably, an enrichment of potential pathobionts (Enterobacteriacee and Streptococcaceae) was found in EGPA, particularly in patients with active disease, while lower levels were found in patients on immunosuppression, compared with non-immunosuppressed ones. Significantly lower amounts of hexanoic acid were found in patients, compared to controls. The analysis of the immune response in the gut mucosa revealed a high frequency of IFN-γ/IL-17-producing T lymphocytes, and a positive correlation between EGPA disease activity and intestinal T-cell levels. Our data suggest that an enrichment in potential intestinal pathobionts might drive an imbalanced inflammatory response in EGPA

Evolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients

Abstract Recurring sequences of genomic alterations occurring across patients can highlight repeated evolutionary processes with significant implications for predicting cancer progression. Leveraging the ever-increasing availability of cancer omics data, here we unveil cancer’s evolutionary signatures tied to distinct disease outcomes, representing “favored trajectories” of acquisition of driver mutations detected in patients with similar prognosis. We present a framework named ASCETIC (Agony-baSed Cancer EvoluTion InferenCe) to extract such signatures from sequencing experiments generated by different technologies such as bulk and single-cell sequencing data. We apply ASCETIC to (i) single-cell data from 146 myeloid malignancy patients and bulk sequencing from 366 acute myeloid leukemia patients, (ii) multi-region sequencing from 100 early-stage lung cancer patients, (iii) exome/genome data from 10,000+ Pan-Cancer Atlas samples, and (iv) targeted sequencing from 25,000+ MSK-MET metastatic patients, revealing subtype-specific single-nucleotide variant signatures associated with distinct prognostic clusters. Validations on several datasets underscore the robustness and generalizability of the extracted signatures

Characterization of the “gut microbiota-immunity axis” and microbial lipid metabolites in atrophic and potential celiac disease

IntroductionPotential celiac disease (pCD) is characterized by genetic predisposition, positive anti-endomysial and anti-tissue transglutaminase antibodies, but a normal or almost normal jejunal mucosa (e.g., minor histological abnormalities without villous atrophy). To gain further insights into basic mechanisms involved in the development of intestinal villous atrophy, we evaluated and compared the microbial, lipid, and immunological signatures of pCD and atrophic CD (aCD).Materials and methodsThis study included 17 aCD patients, 10 pCD patients, and 12 healthy controls (HC). Serum samples from all participants were collected to analyze free fatty acids (FFAs). Duodenal mucosa samples of aCD and pCD patients were taken to evaluate histology, tissue microbiota composition, and mucosal immune response.ResultsWe found no significant differences in the mucosa-associated microbiota composition of pCD and aCD patients. On the other hand, in pCD patients, the overall abundance of serum FFAs showed relevant and significant differences in comparison with aCD patients and HC. In detail, compared to HC, pCD patients displayed higher levels of propionic, butyric, valeric, 2-ethylhexanoic, tetradecanoic, hexadecanoic, and octadecanoic acids. Instead, aCD patients showed increased levels of propionic, isohexanoic, and 2-ethylhexanoic acids, and a lower abundance of isovaleric and 2-methylbutyricacids when compared to HC. In addition, compared to aCD patients, pCD patients showed a higher abundance of isobutyric and octadecanoic acid. Finally, the immunological analysis of duodenal biopsy revealed a lower percentage of CD4+ T lymphocytes in pCD infiltrate compared to that observed in aCD patients. The functional characterization of T cells documented a pro-inflammatory immune response in both aCD and pCD patients, but the pCD patients showed a higher percentage of Th0/Th17 and a lower percentage of Th1/Th17.ConclusionThe results of the present study show, for the first time, that the duodenal microbiota of patients with pCD does not differ substantially from that of aCD; however, serum FFAs and local T cells displayed a distinctive profile between pCD, aCD, and HC. In conclusion, our result may help to shed new light on the “gut microbiota-immunity axis,” lipid metabolites, and duodenal immune response in overt CD and pCD patients, opening new paradigms in understanding the pathogenesis behind CD progression