Bile acid activated receptors: Integrating immune and metabolic regulation in non-alcoholic fatty liver disease

Abstract Bile acids are a family of atypical steroids generated at the interface of liver-intestinal microbiota acting on a ubiquitously expressed family of membrane and nuclear receptors known as bile acid activated receptors. The two best characterized receptors of this family are the nuclear receptor, farnesoid X receptor (FXR) and the G protein-coupled receptor, G protein-coupled bile acid receptor 1 (GPBAR1). FXR and GPBAR1 regulate major aspects of lipid and glucose metabolism, energy balance, autophagy and immunity and have emerged as potential pharmaceutical targets for the treatment of metabolic and inflammatory disorders. Clinical trials in non-alcoholic fatty liver disease (NAFLD), however, have shown that selective FXR agonists cause side effects while their efficacy is partial. Because FXR and GPBAR1 exert additive effects, dual FXR/GPBAR1 ligands have been developed for the treatment of metabolic disorders and are currently advanced to clinical trials. Here, we will review the role of FXR and GPBAR1 agonism in NAFLD and how the two receptors could be exploited to target multiple components of the disease

SNK @ DANKMEMES: Leveraging Pretrained Embeddings for Multimodal Meme Detection

In this paper, we describe and present the results of meme detection system, specifically developed and submitted for our participation to the first subtask of DANKMEMES (EVALITA 2020). We built simple classifiers, consisting in feed forward neural networks. They leverage existing pretrained embeddings, both for text and image representation. Our best system (SNK1) achieves good results in meme detection (F1 = 0.8473), ranking 2nd in the competition, at a distance of 0.0028 from the first classified.In questo articolo, descriviamo e presentiamo i risultati di un sistema di individuazione dei meme, ideato e sviluppato per partecipare al primo subtask di DANKMEMES (EVALITA 2020). Abbiamo realizzato dei semplici classificatori, costituiti da una rete neurale feed-forward: essi sfruttano embedding preesistenti, per la rappresentazione numerica di testo e immagini. Il nostro miglior sistema (SNK1) raggiunge buoni risultati nell’individuazione dei meme (F1 = 0.8473) e si è classificato secondo nella competizione, ad una distanza di 0.0028 dal primo classificato

Status of the EDELWEISS-II experiment

EDELWEISS is a direct dark matter search experiment situated in the low radioactivity environment of the Modane Underground Laboratory. The experiment uses Ge detectors at very low temperature in order to identify eventual rare nuclear recoils induced by elastic scattering of WIMPs from our Galactic halo. We present results of the commissioning of the second phase of the experiment, involving more than 7 kg of Ge, that has been completed in 2007. We describe two new types of detectors with active rejection of events due to surface contamination. This active rejection is required in order to achieve the physics goals of 10-8 pb cross-section measurement for the current phase

Theonella: A Treasure Trove of Structurally Unique and Biologically Active Sterols

: The marine environment is considered a vast source in the discovery of structurally unique bioactive secondary metabolites. Among marine invertebrates, the sponge Theonella spp. represents an arsenal of novel compounds ranging from peptides, alkaloids, terpenes, macrolides, and sterols. In this review, we summarize the recent reports on sterols isolated from this amazing sponge, describing their structural features and peculiar biological activities. We also discuss the total syntheses of solomonsterols A and B and the medicinal chemistry modifications on theonellasterol and conicasterol, focusing on the effect of chemical transformations on the biological activity of this class of metabolites. The promising compounds identified from Theonella spp. possess pronounced biological activity on nuclear receptors or cytotoxicity and result in promising candidates for extended preclinical evaluations. The identification of naturally occurring and semisynthetic marine bioactive sterols reaffirms the utility of examining natural product libraries for the discovery of new therapeutical approach to human diseases

Engineering geology challenges at the Politecnico di Torino

The Engineering Geology area studies the physical geography and geomorphology of the “Environment system”. In particular, Engineering Geology deals with the defense of the soil, territory and civil protection, with attention to landslides, hydrogeology, the study of underground water circulation, the geological-technical survey, geological exploration of the subsoil and thematic cartography, geological and hydrogeological risk; interpretation of aerial photos and satellite images, topographical analysis on digital models of the survey, study of climate changes and their influence on erosion, sedimentation and pedogenesis processes, the study of geothermal systems, the analysis of geological systems related to hydrocarbons and minerals. Research methods include field and laboratory experiments and appropriate numerical modeling software is often used. In conclusion, the aim of this paper should be a review of all engineering geology tematics analysed and studied by Applied Geology Group in Politecnico di Torino

Reciprocal regulation of the bile acid-activated receptor FXR and the interferon-γ-STAT-1 pathway in macrophages

AbstractNuclear receptors are a family of ligand regulated factors that exert homeostatic functions at the interface between metabolic and immune function. The farnesoid X receptor (FXR) is a bile acid sensor expressed in immune cells such as macrophages where it exerts counter-regulatory effects. FXR deficient mice demonstrate disregulated immune response. Expression of FXR is down-regulated in inflamed tissues but the mechanism that leads to FXR down-regulation by inflammatory mediators is unknown. In the present study we have investigated the effect of inflammation-related cytokines on macrophages and demonstrated that INFγ is a potent inhibitor of FXR gene expression/function in macrophages. STAT1 silencing and over-expression experiments demonstrated that FXR repression is mediated by INFγ dependent activation of STAT1. Since IFNγ is a potent activator of STAT1 we searched for STAT1 binding sites in the human FXR genomic and identified a region of the human FXR gene between the second and third exon that contains three hypothetical STAT1 binding sites. RAW 264.7 transiently transfected with an FXR genomic reporter construct which contained the three STAT binding sites responded to IFNγ with a robust decrease in the reporter activity, demonstrating the potent modulation of FXR transcription by IFNγ. Chromatin immunoprecipitation assay revealed that this region was immunoprecipitated following treatment of macrophage cell lines and supershift assay demonstrated that STAT1 was able to bind one of three identified sites. In summary, these results suggest that IFNγ induced STAT1 homodimers modulate the transcriptional repression of FXR gene in macrophages during inflammation-related cytokines

Hydrogen sulphide induces μ opioid receptor-dependent analgesia in a rodent model of visceral pain

<p>Abstract</p> <p>Background</p> <p>Hydrogen sulphide (H₂S) is a gaseous neuro-mediator that exerts analgesic effects in rodent models of visceral pain by activating K_ATPchannels. A body of evidence support the notion that K_ATPchannels interact with endogenous opioids. Whether H₂S-induced analgesia involves opioid receptors is unknown.</p> <p>Methods</p> <p>The perception of painful sensation induced by colorectal distension (CRD) in conscious rats was measured by assessing the abdominal withdrawal reflex. The contribution of opioid receptors to H₂S-induced analgesia was investigated by administering rats with selective μ, κ and δ opioid receptor antagonists and antisenses. To investigate whether H₂S causes μ opioid receptor (MOR) transactivation, the neuronal like cells SKNMCs were challenged with H₂S in the presence of MOR agonist (DAMGO) or antagonist (CTAP). MOR activation and phosphorylation, its association to β arrestin and internalization were measured.</p> <p>Results</p> <p>H₂S exerted a potent analgesic effects on CRD-induced pain. H₂S-induced analgesia required the activation of the opioid system. By pharmacological and molecular analyses, a robust inhibition of H₂S-induced analgesia was observed in response to central administration of CTAP and MOR antisense, while κ and δ receptors were less involved. H₂S caused MOR transactivation and internalization in SKNMCs by a mechanism that required AKT phosphorylation. MOR transactivation was inhibited by LY294002, a PI3K inhibitor, and glibenclamide, a K_ATPchannels blocker.</p> <p>Conclusions</p> <p>This study provides pharmacological and molecular evidence that antinociception exerted by H₂S in a rodent model of visceral pain is modulated by the transactivation of MOR. This observation provides support for development of new pharmacological approaches to visceral pain.</p

Assessment of groundwater geochemistry and human health risk of an intensively cropped alluvial plain, NW Italy

Groundwater chemistry data play an essential role to identify the water quality status and assess the exposure to human health. Therefore, in the present research, combined approaches used to assess the geochemistry, sources of ions and human health risk in the groundwater of the Tronzano Vercellese. Moreover, a geographic information system (GIS) technique was applied to identify locations have the most risk to human health. The results of the present study show that the groundwater samples had sequence of Ca2þ>Mg2þ>Naþ>Kþ in cationic, HCO3 >SO4 >2>NO3 >Cl>F in anionic and Zn> Fe > Ba> Ni> Mn> Cu> Cr > As in metals abundance. The hydrogeochemical approaches indicate that the major ions chemistry was mainly controlled by the weathering of carbonate and silicate minerals, and ion-exchange reactions. Furthermore, statistical analysis reveals that the non-lithogenic origin was the primary sources of some elements (Mn, Zn, Ba, NO3 and Kþ) in the water samples. The hazard quotient (HQ) and hazard index (HI) were estimated to assess the risk to human health using the United States Environmental Protection Agency (USEPA) methods. Estimated HQ and HI values were higher for the child as compared to the adult and suggesting that the elements posed little hazard individually in the case of the child

A Grid platform for the European Civil Protection e-Infrastructure: the Forest Fires use scenario

During the full cycle of the emergency management, Civil Protection operative procedures involve many actors belonging to several institutions playing different roles. In this context the sharing of information is a vital requirement to make correct and effective decisions. Therefore a European-wide technological infrastructure providing a distributed and coordinated access to different kinds of resources (data, information, services, expertise, etc.) could enhance existing Civil Protection applications and even enable new ones. In the recent years Grid technologies have reached a mature state providing a platform for secure and coordinated resource sharing between the participants in the so-called Virtual Organizations. Moreover the Earth and Space Sciences Informatics provide the conceptual tools for modelling the geospatial information shared in Civil Protection applications during its entire life cycle. Therefore a European Civil Protection e-infrastructure could be based on a Grid platform enhanced with Earth Sciences specific services. However Civil Protection applications stress the requirements of Earth Sciences research applications, for example in terms of real-time support. Therefore a set of high-level services specifically tailored for such applications must be built on top of the Grid platform. As a result of a requirement analysis, the FP6 project CYCLOPS has proposed an architectural framework for the future European Civil Protection e-Infrastructure. In this architecture a layer of high-level services tailored to Civil Protection applications is built on top of the EGEE Grid middleware. This architectural approach has been tested implementing a prototype of a grid-enabled RISICO, the application for wild fire risk assessment used by the Italian Civil Protection