Plasma levels of nitric oxide related amino acids in demented subjects with Down syndrome are related to neopterin concentrations

Subjects with Down syndrome (DS) have abnormalities in virtually all aspects of the immune system and almost all will be affected with Alzheimer’s disease (AD). It is thought that nitric oxide (NO) is involved in the pathophysiology of AD. In the present study, including a total of 401 elderly DS subjects, the spectrum of plasma amino acids and neopterin was investigated and related to development of AD. Concentrations of nearly all amino acids in DS subjects differed significantly from those of healthy controls. Neopterin was increased in DS subjects, especially in dementia. The production of NO as reflected by an increased citrulline/arginine ratio (Cit/Arg ratio) was enhanced during development of clinical dementia. Neopterin concentrations correlated to the Cit/Arg ratio only in the group of prevalent demented subjects (ρ = 0.48, P = 0.006). The results of this study are suggestive for an increase in oxidative processes in DS subjects with AD

Recurrent ANNs for Failure Predictions on Large Datasets of Italian SMEs

The prediction of failure of a firm is a challenging topic in business research. In this paper, we consider a machine learning approach to detect the state of asset shortfall in the Italian small and medium-sized enterprises’ context. More precisely, we use the recurrent neural networks to predict the insolvency of firms. The huge dataset we study allows us to overcome problems of distortions given by smaller sample sizes. The observed sample comes from AIDA database, and consider thirty variables replicated for five years. The main result is that recurrent neural networks outperform the multi-layer perceptron architecture used as benchmark. The obtained accuracy scores are in line with those found in the literature, and this suggests that the use of new techniques such as those tried out in this study could produce even better results

TGF-β signalling defect is linked to low CD39 expression on regulatory T cells and methotrexate resistance in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune arthropathy characterized by chronic articular inflammation. Methotrexate (MTX) remains the first-line therapy for RA and its anti-inflammatory effect is associated with the maintenance of high levels of extracellular adenosine (ADO). Nonetheless, up to 40% of RA patients are resistant to MTX treatment and this is linked to a reduction of CD39 expression, an ectoenzyme involved in the generation of extracellular ADO by ATP metabolism, on circulating regulatory T cells (Tregs). However, the mechanism mediating the reduction of CD39 expression on Tregs is unknown. Here we demonstrated that the impairment in TGF-β signalling lead to the reduction of CD39 expression on Tregs that accounts for MTX resistance. TGF-β increases CD39 expression on Tregs via the activation of TGFBRII/TGFBRI, SMAD2 and the transcription factor CREB, which is activated in a p38-dependent manner and induces CD39 expression by promoting ENTPD1 gene transcription. Importantly, unresponsive patients to MTX (UR-MTX) show reduced expression of TGFBR2 and CREB1 and decreased levels of p-SMAD2 and p-CREB in Tregs compared to MTX-responsive patients (R-MTX). Furthermore, RA patients carrying at least one mutant allele for rs1431131 (AT or AA) of the TGFBR2 gene are significantly (p = 0.0006) associated with UR-MTX. Therefore, we have uncovered a molecular mechanism for the reduced CD39 expression on Tregs, and revealed potential targets for therapeutic intervention for MTX resistance

Thiotaurine protects mouse cerebellar granule neurons from potassium deprivation-induced apoptosis by inhibiting the activation of caspase-3

Taurine (2-aminoethanesulphonic acid) is an endogenous amino acid that has a number of protective roles in most mammalian cells, including modulation of cytoplasmic calcium levels, antioxidant effects and protection against mitochondrial dysfunction and endoplasmic reticulum stress associated with neurological disorders. Thiotaurine (2-aminoethane thiosulfonate), a molecule structurally related to hypotaurine and taurine, counteracts the damaging effect of oxidants and prevents apoptosis of human neutrophils. In this study we have compared the effect of taurine and thiotaurine in protecting cerebellar granule neurons (CGNs) from apoptotic death. Two experimental paradigms were exploited to induce apoptosis: i) CGNs were continuously cultured in 5 mM K+-containing medium up to 6 days in the presence or absence of 1 mM either taurine or thiotaurine (chronic paradigm); ii) CGNs were cultured in 25 mM K+-containing medium for 6 days and then shifted to a 5 mM K+-containing medium in the presence or absence of 1 mM either taurine or thiotaurine (acute paradigm). In the first condition, CGNs survive up to 5 days, and then start to die; in the second condition, CGNs nicely differentiate elongating neurites but enter apoptosis within 30 min when shifted to the 5 mM K+-containing medium. These assays showed that taurine and thiotaurine counteracted the apoptotic death induced by low potassium in both the acute and chronic paradigms. However, while they displayed a similar efficacy in the chronic paradigm, the thiotaurine showed a significantly higher (20 %) efficacy compared to taurine in the acute paradigm. This finding pinpoints the thiotaurine as a powerful anti-apoptotic molecule in neurons that are fully differentiated and have established synaptic connections