Editors’ Introduction. Futures: Imagining the World of Tomorrow

From 12 to 17 September 2016 in Cuneo (Italy) took place the 9th edition of the international Summer School organized by the Centro Studi sul Pensiero Contemporaneo (CeSPeC). The event revolved around the topic of the “future”, which was analysed from different interdisciplinary perspectives and gave rise to stimulating conversation. In this introduction we provide an overview of the topic and of the reflections stemming from that event

Functional Role of the Third Cytoplasmic Loop in Muscarinic Receptor Dimerization

By means of the expression of two chimeric receptors, alpha2/m3 and m3/alpha2, in which the carboxyl-terminal receptor portions, containing transmembrane (TM) domains VI and VII, were exchanged between the alpha2C adrenergic and the m3 muscarinic receptor, Maggio et al. (Maggio, R., Vogel, Z., and Wess, J. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 3103-31073) demonstrated that G protein-linked receptors are able to interact functionally with each other at the molecular level to form (hetero)dimers. In the present study we tested the hypothesis that interaction between receptors might depend on the presence of a long third intracellular (i3) loop and that shortening this loop could impair the capability of receptors to form dimers. To address this question, we initially created short chimeric alpha2 adrenergic/m3 muscarinic receptors in which 196 amino acids were deleted from the i3 loop (alpha2/m3-short and m3/alpha2-short). Although co-transfection of alpha2/m3 and m3/alpha2 resulted in the appearance of specific binding, the co-expression of the two short constructs (alpha2/m3-short and m3/alpha2-short), either together or in combination, respectively, with m3/alpha2 and alpha2/m3 did not result in any detectable binding activity. In another set of experiments, a mutant m3 receptor, m3/m2(16aa), containing 16 amino acids of the m2 receptor sequence at the amino terminus of the third cytoplasmic loop, which was capable of binding muscarinic ligands but was virtually unable to stimulate phosphatidylinositol hydrolysis, was also mutated in the i3 loop, resulting in the m3/m2(16aa)-short receptor. Although co-transfection of m3/m2(16aa) with a truncated form of the m3 receptor (m3-trunc, containing an in frame stop codon after amino acid codon 272 of the rat m3 sequence) resulted in a considerable carbachol-stimulated phosphatidylinositol breakdown, the co-transfection of m3/m2(16aa)-short with the truncated form of the m3 receptor did not result in any recovery of the functional activity. Thus, these data suggest that intermolecular interaction between muscarinic receptors, involving the exchange of amino-terminal (containing TM domains I-V) and carboxyl-terminal (containing TM domains VI and VII) receptor fragments depends on the presence of a long i3 loop. One may speculate that when alternative forms of receptors with a different length of the i3 loop exist, they could have a different propensity to dimerize

The Paired Activation of the Two Components of the Muscarinic M3 Receptor Dimer Is Required for Induction of ERK1/2 Phosphorylation *

Muscarinic M(3) receptors stimulate ERK1/2, the mitogen-activated protein kinase pathway. A mutant of the muscarinic M(3) receptor in which most of the third intracellular (i3) loop had been deleted (M(3)-short) completely lost the ability to stimulate the ERK1/2 phosphorylation in COS-7 cells. This loss was evident despite the fact that the receptor was able to couple efficiently to the phospholipase C second messenger pathway. In co-transfected cells, M(3)-short greatly reduced the ability of M(3) to activate ERK1/2. In another set of experiments we tested the ability of a mutant M(3)/M(2)(16aa) receptor, in which the first 16 amino acids of the i3 loop of the M(3) receptor were replaced with the corresponding segment of the muscarinic M(2) receptor to stimulate ERK1/2 phosphorylation. This mutant is not coupled to Galpha(q), but it is weakly coupled to Galpha(i). Despite its coupling modification this receptor was able to stimulate ERK1/2 phosphorylation. Again, M(3)-short greatly reduced the ability of M(3)/M(2)(16aa) to activate ERK1/2 in co-transfected cells. Similar results were obtained in stable-transfected Chinese hamster ovary (CHO) cells lines. In CHO M(3) cells carbachol induced a biphasic increase of ERK1/2 phosphorylation; a first increase at doses as low as 0.1 microm and a second increase starting from 10 microm. In CHO M(3)-short and in double-transfected CHO M(3)/M(3)-short cells we observed only the lower doses increase of ERK1/2 phosphorylation; no further increase was observed up to 1 mm carbachol. This suggests that in double-transfected CHO cells M(3)-short prevents the effect of the higher doses of carbachol on the M(3) receptor. In a final experiment we tested the ability of co-transfected chimeric alpha(2)/M(3) and M(3)/alpha(2) receptors to activate the ERK1/2 pathway. When given alone, carbachol and, to a lesser extent, clonidine, stimulated the coupling of the co-transfected chimeric receptors to the phospholipase C second messenger pathway, but they were unable to stimulate ERK1/2 phosphorylation. On the contrary, a strong stimulation of ERK1/2 phosphorylation was observed when the two agonists were given together despite the fact that the overall increase in phosphatidylinositol hydrolysis was not dissimilar from that observed in cells treated with carbachol alone. Our data suggest that the activation of the ERK1/2 pathway requires the coincident activation of the two components of a receptor dimer

Sound-Induced Flash Illusions Support Cortex Hyperexcitability in Fibromyalgia

properly cited. Objectives. Fibromyalgia (FM) is characterized by spontaneous chronic widespread pain in combination with hyperalgesia to pressure stimuli. Sound-induced flash illusions (SIFIs) reflect cross-modal interactions between senses allowing to assess a visual cortical hoerexcitability (VCH) by evaluating the fission and fusion illusions disruption. The aims of the present study were to explore whether SIFIs are perceived differently in patients with fibromyalgia as compared to healthy controls (HCs) and how migraine affects fission and fusion illusions in fibromyalgia. Methods. A single flash (F) accompanied by 0 to 4 beeps (B) was presented to induce the fission illusion while multiple flash (i.e., 2 to 4) accompanied by 0 or 1 beep was presented to induce fusion illusion. The mean number of perceived flashes in fission and fusion illusion trials was compared between the groups (i.e., FM, FM with migraine, and HCs) using repeated-measures analysis of variance. Medication history was recorded along with the administration of Fibromyalgia Impact Questionnaire and Hospital Anxiety and Depression scales. Results. Twenty-four patients with FM (mean age 51, 2 +/- 10, 6 years; 22 females), seventeen patients with FM and migraine without aura (mean age 47.8 +/- 11.4 years; 16 females; 13 chronic, 4 episodic migraine), and forty-one age-and sex-matched HCs (mean age 47.3 +/- 6.9 years; 34 females) participated in the study. Fission and fusion illusory effects were detected in all the participants. However, in FM patients, the fission illusion was reduced and almost abolished as compared to HCs (1F1B, p = 0.02; 1F2B, p < 0.0001; 1F3B, p < 0.0001; 1F4B, p = 0.0001), while there were no differences between groups in fusion trials. Migraine did not affect the fission and the fusion illusions. Conclusion. Results from this study confirm that patients with FM have a VCH suggesting that the pathological changes in cortical excitability might have important roles in the pathophysiology of FM. SIFI represents a noninvasive behavioral tool for the exploration of cross-sensory functional interplay

On the use of information and infrastructure technologies for the smart city research in Europe: a survey

The Smart City paradigm has become one of the most important research topics around the globe. Particularly in Europe, it is considered as a solution for unstoppable increase of high density urban environments and the European Commission has included the Smart City research as one of the key objectives for the FP7 (Seventh Framework Program) and H2020 (Horizon 2020) research initiatives. As a result, a considerable amount of quality research, with particular emphasis on information and communication technologies, has been produced. In this paper, we review the current efforts dedicated in Europe to this research topic. Particular attention is paid in the review to the platforms and infrastructure technologies adopted to introduce the Internet of Things into the city, taking into account the constraints and harshness of urban environments. Furthermore, this paper also considers the efforts in the experimental perspective, which includes the review of existing Smart City testbeds, part of wider European initiatives such as FIRE (Future Internet Research and Experimentation) and FIWARE. Last but not least, the main efforts in providing interoperability between the different experimental facilities are also presented.This work was funded in part by the European Union’s Horizon 2020 Programme of the FESTIVAL project (Federated Interoperable Smart ICT Services Development and Testing Platforms) under grant agreement 643275, and from the Japanese National Institute of Information and Communications Technology

Engineering sciences:: pharmacokinetics and pharmacodynamics as an inter- and multidisciplinary field

Amongst the entire potential spectrum of expansion of the engineering sciences as an omnipresent field, we might point out the studies of drugs, applied pharmacology, as a good candidate for receiving attention. The common problematic encountered in the literature faced by the industry of drugs is the high cost for drug development and systematic approaches are demanded. On the hope to bring the discussions to engineering’s territory, we borrow several insights from mathematical modeling; it is presented a simple case study, tumor treatment using optimal control, we shall see that it is possible with simple tools already standard in engineering to design an optimal regimen for the tumor therapy, given that the tumor respects our model. On the example presented, we shall see that tools already part of (industrial) production engineering, with exception of optimal control theory, is enough for getting insights. The ideas discussed herein could diminish the cost of drug development if properly extended. As any endeavor, we have challenges, such as to gain the credibility necessary for really using those models in the academy and industry

FESTIVAL: heterogeneous testbed federation across Europe and Japan

FESTIVAL is an H2020 EU-Japan collaborative project that aims to federate heterogeneous testbeds, making them interoperable and building an “Experimentation as a Service” (EaaS) model. Going beyond the traditional nature of experimental facilities, related to computational and networking large scale infrastructures, FESTIVAL testbeds have heterogeneous nature and in order to be federated they have been clustered in four categories: “Open Data” (i.e. open datasets), “IoT” (i.e. sensors and actuators), “IT” (i.e. computational resources) and “Living Labs” (i.e. people). Considering that every testbed category provides specific resources, the main challenge for FESTIVAL is to develop a platform that can allow experimenters to access very different assets in an homogeneous and transparent way, supporting them in the phases of the experiments. The FESTIVAL architecture, based on a multi-level federation approach, proposes a solution to this problem providing also a set of functionalities to manage and monitor the experiments. FESTIVAL tools, also, include the possibility to access FIWAREGeneric Enablers allowing to deploy predefined components to address specific needs in the experimentation (e.g. data analysis, big data management etc.). The FESTIVAL platform will be tested on three different smart city domains across Japan and Europe: smart energy, smart building and smart shopping.This work was funded in part by the European Union’s Horizon 2020 Programme of the FESTIVALproject (Federated Interoperable Smart ICT Services Development and Testing Platforms) under grant agreement no. 643275, and by the Japanese National Institute of Information and Communications Technology

Ultra-sonografia com Doppler colorido e uso de contraste na diferenciação dos tumores ovarianos

The objective of this study was to differentiate benign ovarian tumors from malignant ones before surgery using color and pulsed Doppler sonography, and to compare results obtained before and after use of contrast medium, thereby verifying whether contrast results in an improvement in the diagnostic sensitivity. METHODS: Sixty two women (mean age 49.9 years) with ovarian tumors were studied, 45 with benign and 17 with malignant tumors. All women underwent a transvaginal color Doppler ultrasonographic exam. A study of the arterial vascular flow was made in all tumor areas, as well as an impedance evaluation of arterial vascular flow using the resistance index. RESULT: Localization of the vessels in the tumor revealed a greater proportion of malignant tumors with detectable internal vascular flows (64%) than benign tumors with such flows (22%). There was a considerable overlap of these findings. The use of contrast identified a greater number of vessels with confirmation in the totality of tumors, but did not improve the Doppler capacity in tumoral differentiation. Malignant tumors presented lower values of resistance index than the benign ones, whether or not contrast was used. The cutoff value for resistance index that better maximized the Doppler sensitivity and specificity was 0.55. Through this value, an increase of the sensitivity after contrast use was obtained, varying from 47% to 82%, while specificity remained statistically unchanged. CONCLUSION: Although the injection of a microbubble agent improved the sensitivity of the method detecting vascularization of tumors, a positive finding for vascularization by this method was not clinically useful in the differentiation of benign and malignant ovarian tumors.O objetivo deste estudo foi diferenciar tumores ovarianos benignos e malignos antes da cirurgia através da ultra-sonografia com uso de Doppler colorido pulsátil e comparar os resultados obtidos antes e após o uso de contraste. MÉTODO: Foram estudadas sessenta e duas mulheres (idade média de 49,9 anos) com tumores ovarianos, sendo 45 benigos e 17 malignos. Todas foram submetidas a ultra-sonografia transvaginal com Doppler colorido. A pesquisa de fluxo vascular foi realizado em todas as áreas tumorais, assim como a avaliação da impedância através do índice de resistência. RESULTADOS: A localização dos vasos no tumor revelaram uma maior proporção de fluxo vascular interno detectável nos tumores malignos (64%) do que nos tumores benignos (22%). Houve entretanto uma considerável sobreposição destes achados. O uso de constrate foi capaz de identificar um grande número de vasos na totalidade dos tumores, mas não melhorou a capacidade do Doppler na diferenciação entre tumores benignos e malignos. Os tumores malignos apresentaram valores mais baixos de índice de resistência.IR do que os benignos, independentemente do uso de contraste. O valor de corte do índice de resistência. que maximizou a sensibilidade e a especificidade do Doppler foi de 0,55. Com este valor foi obtido um aumento na sensibilidade após o uso de contraste, variando de 47% a 82 %, enquanto a especificidade se manteve equivalente. CONCLUSÃO: Embora a injeção de agentes produtores de microbolhas aumentem a sensibilidade do método na diferenciação da natureza do tumor, este valor não se mostrou clinicamente util na avaliação de tumores ovarianos

Atypical antipsychotics and metabolic syndrome : from molecular mechanisms to clinical differences

Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophre-nia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their ac-tions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′ AMP-activated protein kinase (AMPK) activity, thus producing a supra-physiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olan-zapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasi-done and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.Publisher PDFPeer reviewe

The accuracy of burn depth diagnosis: Clinical assessment before and after enzymatic debridement

Abstract Introduction The most common technique used to determine burn depth is clinical assessment by experienced burn surgeons, although this has been shown to be reliable in only 60–75% of the cases. Overestimation of burn depth may result in needles surgery, while burn depth underestimation can led to an increased length of stay in the hospital, risk of contracture and hypertrophic scar formation. The aim of this study was to assess the clinical evaluation of burn depth before and after enzymatic debridement with Nexobrid®. Methods The study model was retrospective. 69 patient records were collected at our burn units, from Jan 2018 to Jan 2019. Each target wound was directly assessed by a single expert physician before and after enzymatic debridement. It was investigated whether the expert, by single wound, would have indicated the need for skin grafts before treatment with Nexobrid® and after treatment. Results Prior to treatment with Nexobrid®, the expert physician assessed that a graft was necessary for 47/69 patients (68.1%). Following debridement, the same expert deemed that the patients needing a graft were 19/69 (27.5%); analysing K-agreement, a 40.6% discrepancy between the pre and post-treatment opinion with Nexobrid® was observed. Discussion The use of Nexobrid® enzymatic debridement can positively affect burn depth clinical assessment, increasing its specificity and sensitivity, without any need for delay. This can lead to a significant change in clinical practice, minimizing the use of surgery, therefore increasing quality and precision of the reconstructive phase