668 research outputs found
Pharmacological and biotechnological in vitro approaches unveil the role of GPR17 signaling in regulating the timing of oligodendroglial differentiation
No full textBackground and Purpose - In the adult central nervous system there are many oligodendrocyte precursor cells (OPCs) that serve as the primary source of remyelinating cells in demyelinated lesions. Knowledge of the mechanisms regulating OPC maturation is needed to unveil novel pharmacological targets in demyelinating diseases. The G-protein-coupled membrane receptor GPR17, activated by both uracil nucleotides and cysteinyl-leucotrienes [1], has recently emerged as an important player in oligodendrogliogenesis [2,3]. It has been previously reported that GPR17 presence is restricted to NG2+-OPCs at early differentiation stages and is completely segregated from that of myelin proteins [4]. Here, we used purified primary OPCs from rat cortical parenchyma to assess the functional consequences of GPR17 modulation by either pharmacological or biotechnological approaches on the differentiation program of these cells.
Methods and Results - OPCs were exposed to the GPR17 agonists UDP-glucose, UDP and LTE4 for 48 hours. The degree of OPC differentiation was assessed on fixed cultures by immunostaining with an antibody against Myelin basic protein (MBP), a marker of mature oligodendrocytes. Data show that all these agonists increase the proportion of MBP+ cells compared to controls, suggesting acceleration of cell maturation by promoting receptor activation. Secondly, transfection experiments with fluorescent plasmids, enabling either silencing or over-expression of GPR17 were performed to univocally correlate the expression of this receptor with cell shape changes and phenotype acquisition during oligodendroglial maturation. Preliminary results show that suppression of GPR17 expression at early differentiation stages reduces the number of MBP+cells in culture, indicating that its silencing impairs the normal program of OPC differentiation.
Conclusions - Globally, these data point at GPR17 as a key regulator of oligodendrogliogenesis and at GPR17 ligands as extrinsic local regulators of OPCs under physiological conditions and during myelin repair.
References
[1] P. Ciana, M. Fumagalli, M.L. Trincavelli, C. Verderio, P. Rosa, D. Lecca, S. Ferrario, C. Parravicini, V. Capra, P. Gelosa, U. Guerrini, S. Belcredito, M. Cimino, L. Sironi, E. Tremoli, G.E. Rovati, C. Martini, M.P. Abbracchio, The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinil-leukotrienes receptor. EMBO J, 19, 4615-2627, 2006.
[2] D. Lecca, M.L. Trincavelli, P. Gelosa, L. Sironi, P. Ciana, M. Fumagalli, G. Villa, C. Verderio, C. Grumelli, U. Guerrini, E. Tremoli, P. Rosa, S. Cuboni, C. Martini, A. Buffo, M Cimino, M.P. Abbracchio, The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PloS One, 10, e3579, 2008.
[3] Y. Chen, H. Wu, S. Wang, H. Koito, J. Li, F. Ye, J. Hoang, S.S. Escobar, A. Gow, H.A. Arnett, B.D. Trapp, N.J. Karandikar, J. Hsieh, Q.R. Lu, The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nature Neuroscience, 12, 1398-1406.
[4] M. Fumagalli, S. Daniele, D. Lecca, P.R. Lee, C. Parravicini, R.D. Fields,P. Rosa, F. Antonucci, C. Verderio, M.L Trincavelli, P. Bramanti, C. Martini, M.P. Abbracchio, Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. The Journal of biology chemistry,12, 10593-10604
Real trubles and financial veil: the current accounts dilemma
No full textThis paper integrates a few past inputs of the author on the causes for the present international economic downturn and tries to identify some of its main structural causes. The deficit of the balance of payments current account, in fact, with the subsequent creation of public and private certificates of indebtness, may seem to have generated the conditions for the turmoil on the financial and real markets through the creation of sometimes disputable financial instruments
Synthesis and molecular modeling of purine ribonucleotides as potential ligands of the human G protein-coupled receptor 17 (GPR17)
No full textGPCRs (G Protein-Coupled Receptors) are important drug targets in medicinal chemistry [1]. The GPR17 receptor, phylogenetically related to both purinergic P2Y and CysLT receptors, is usually over-expressed in the damaged brain tissue and is involved in various disorders characterized by demyelination, such as multiple sclerosis and stroke. Experimental data have shown that it is responsive to both agonists (e.g. nucleotides and their adducts) and antagonists (e.g. Cangrelor and Montelukast) [2]. Therefore, the human GPR17 receptor is a promising therapeutic target for treatment of neurodegenerative diseases [3].
This evidence prompted us to perform docking studies aided by molecular modeling on a homology model (based on P2Y1 receptors). Among the selected molecules, 8-methylaminoinosinic acid (1) and three N2-alkyl/acyl derivatives of guanylic acid (2-4) emerged as the best potential ligands.
As a result, their synthesis was carried out. Compound 1 was obtained by direct phosphorylation of 8-methylaminoinosine, previously prepared by amination of 8-bromoinosine. In the case of 2, position N2 of the purine ring was activated as a bromo derivative and subjected to displacement with n-octylamine. As for 3 and 4, N2-acylations were performed by treatment with a proper acyl chloride or anhydride through a transient protection strategy. Compounds 2, 3 and 4 were obtained as 2’,3’-O-isopropylidene adducts of the corresponding nucleotides.
Binding assays will be carried out by Surface Plasmon Resonance (SPR) [4], which has been demonstrated as a reliable technique for the systematic identification of agonists and antagonists of GPCRs, including GPR17 as recently demonstrated by our group [5].
[1] D. Wacker, R. C. Stevens, B. L. Roth, Cell 2017, 170, 414-427.
[2] P. Ciana, M. Fumagalli, M.L. Trincavelli, C. Verderio, P. Rosa, D. Lecca, S. Ferrario, C. Parravicini, V. Capra, P. Gelosa, U. Guerrini, S. Belcredito, M. Cimino, L. Sironi, E. Tremoli, G.E. Rovati, C. Martini and M.P. Abbracchio, EMBO J 2006, 25, 4615-4627.
[3] G. Marucci, D. Dal Ben, C. Lambertucci, A. Marti Navia, A. Spinaci, R. Volpini and M. Buccioni, Expert Opin. Ther. Pat. 2019, 29, 85-95.
[4] D.-S. Wang, S.-K. Fan, Sensors 2016, 16, 1175-1192.
[5] D. Capelli, C. Parravicini, G. Pochetti, R. Montanari, C. Temporini, M. Rabuffetti, M. L. Trincavelli, S. Daniele, M. Fumagalli, S. Saporiti, E. Bonfanti, M. P. Abbracchio, I. Eberini, S. Ceruti, E. Calleri, S. Capaldi, Front. Chem. 2020, 7, 910
Disavanzo commerciale Usa e crisi finanziaria internazionale
No full textIl lavoro mette a fuoco come l'espansione della "finanza strutturata" e, in particolare, dei derivati abbia determinato la crisi che, dal 2007, sconvolge il sistema finanziario e l'economia reale a livello mondiale. Il protratto deficit dei saldi della bilancia dei pagamenti corrente degli Usa ha determinato, in particolare, l'esigenza di offrire , ai paesi cronicamente in avanzo, prodotti finanziari che si potessero considerare "sicuri"
Darwinismo e pragmatismo. La filosofia evoluzionistica di Chauncey Wright
No full textThe Darwinian evolutionary theory was a real revolution, not only in biology and, generally, in scientific fields, but even in philosophical and epistemological thought. However, in the years that followed the publication of The Origin of Species (1859), virtually nobody, among scientists and philosophers, agreed with the principle of natural selection put forward by Darwin as the main explanation of the evolutionary process. This happened because Darwin’s theory was quite opposed to the “orthodox” view behind natural sciences and the philosophy of nature both in Europe and in America.
Natural theology was taught in every school, academy, college, and it claimed that all the species in nature are created by God for a good purpose or a general design, are fixed in time, and they are already fitted to their environment from the beginning. Some theologians could account for organic forms by evolution to a certain degree, but all of them agreed on the “argument from design” and to the idea that man was «the glory and the supreme king of the natural realm», as Darwin ironically wrote.
One of the few that stood against this background and followed Darwin in his “struggle” against the teleological and anthropocentric interpretation of natural beings was an American philosopher from Cambridge whose name was Chauncey Wright.
Wright (1830-1875) was the well loved master of famous thinkers as William James, Charles Sanders Peirce, or Oliver Wendell Holmes at the “Metaphysical Club” in Cambridge, now considered the birth place of American Pragmatism. Wright started from the William Hamilton’s philosophy and then, in the 1860s, rejected it in favour of the utilitarianism of Bentham, James Mill and John Stuart Mill.
When Darwin’s Origin arrived to America, in 1860, he immediately became a firm supporter of the evolutionary theory. To him, the principle of natural selection was just an application of the Mills’ utilitarian philosophy and, moreover, it was even an improvement of it: e.g., the principle of natural selection could shed new light on the origin of different complex human feelings, ideas, behaviours, whereas the principles of mental association, which were the basis of the utilitarian ethics, were very vague and generic on these genetic problems.
For these reasons Wright thoroughly studied the Darwinian theory for ten years and then he wrote some articles on this topic in the early 1870s. Three of them aimed to take issue with Alfred Russell Wallace and George Mivart’s arguments against the principle of natural selection, and they were so well conducted that Darwin himself thanked Wright and decided to publish one of them in England as a pamphlet at his own expenses. The last of these articles on evolution, titled The Evolution of Self-Consciousness (1873), is the most important of the series. After the death of this author, in 1875, his friends collected almost all his published works in a book entitled Philosophical Discussions (1877) and most of his Letters (1878).
In general, until now, Chauncey Wright’s philosophy has been obscured by the more famous thought of the American Pragmatists, such as Peirce, James, Dewey. Not many scholars wrote on this philosopher and, among them, those who studied his philosophy were more interested in comparing it to the Pragmatist one, rather than in directly elucidating its basic principles and in deeply exploring its theoretical features. For these reasons Edward Madden, the most important Wright scholar, named him a “forgotten philosopher”. At present, only one of Wright’s articles (The evolution of self-consciousness, 1873) has been translated into Italian, and, in general, this thinker is almost unknown in Italy.
On the contrary, my work sets out to prove that Wright’s philosophy is not only fundamental to well understanding the origin and the roots of American Pragmatism, but it is also very important in order to focus on the most interesting philosophical implications of the Darwinian evolutionary theory. In particular, my thesis examines the new epistemology worked out by Wright, which, beginning from a deep analysis of Darwin’s theory, highlighted the still unseen importance of the principle of “the new uses for old functions”. In his stressing the significance of this principle, Wright showed to conceive the evolutionary process in a very similar way, in its main features, to the one advanced by some modern biologists, such as, for example, Gould, Eldredge or Lewontin.
As Wright did a century and a half ago, the above mentioned biologists highlight the importance of this mechanism of new uses for old functions, or, as they call this transformational principle, “exaptations”, in order to go beyond an “adaptationist” or “panselectionist” interpretation of the Darwinian theory.
This pluralistic view, as a working hypothesis, is very effective in its approach to the theoretical problems, especially when Wright applied it on the very classic philosophical question of the nature and of the origin of self-awareness. The main role of these new uses of old powers (like “memory” or “attention”) in relation to the new importance accorded by Wright to the habits and to the use of signs, establishes that Wright’s approach to the problem of the evolution of self-consciousness is a very new one, as it appears to be an interesting combination of an original (and modern) version of Darwinism and an incipient kind of Pragmatism. Nowadays, the solution developed by Wright in his approach to the question of the “human”, could be useful in philosophy and biology to better think and to shed new light on this very controversial and ancient riddle, namely, the origin of language and the evolution of human mind from an evolutionary point of view
A reduced-precision streaming SpMV architecture for Personalized PageRank on FPGA
No full textSparse matrix-vector multiplication is often employed in many data-analytic workloads in which low latency and high throughput are more valuable than exact numerical convergence. FPGAs provide quick execution times while offering precise control over the accuracy of the results thanks to reduced-precision fixed-point arithmetic. In this work, we propose a novel streaming implementation of Coordinate Format (COO) sparse matrix-vector multiplication, and study its effectiveness when applied to the Personalized PageRank algorithm, a common building block of recommender systems in e-commerce websites and social networks. Our implementation achieves speedups up to 6x over a reference floating-point FPGA architecture and a state-of-the-art multi-threaded CPU implementation on 8 different data-sets, while preserving the numerical fidelity of the results and reaching up to 42x higher energy efficiency compared to the CPU implementation
La subordinazione tra legislatore e giurisprudenza costituzionale
No full textL’intervento normativo in tema di collaborazioni di cui al d. lgs. 81/15, con i numerosi problemi interpretativi che esso pone, dà l’occasione per tornare sul tema della subordinazione. L’articolo se ne occupa da tre prospettive: innanzitutto ripercorrendo il dialogo tra legislatore e corte costituzionale per vedere se e quali limiti sono imposti al primo; poi analizzando come il legislatore ha affrontato la questione della fattispecie ed infine verificando le ricadute che le norme del decreto 81/15, sia per quello che disciplinano sia per quello che abrogano, possono aver sulla nozione di lavoratore subordinato
MITRAL ANNULOPLASTY RING
No full textA mitral annuloplasty ring composed of a D-shaped annular structure and made of rigid or semi-rigid material, a coating of the annular structure made of inert tissue and suited to be fixed with sutures to the heart tissues, and a pair of movable and sliding metal or plastic strips positioned in a folded conformation inside the annular structure and having a first end fixed to a rectilinear or circular portion of the annular structure and a second end resting on a curved portion of the annular structure
Exploiting FPGAs from higher level languages a signal analysis case study
No full textField Programmable Gate Arrays (FPGAs) are usually perceived as difficult to exploit due to the High Level of expertise required to program them. In the last years, the major FPGAs vendors have produced different High Level Synthesis (HLS) tools to help programmers during the flow of acceleration of their algorithms through the hardware architecture. However, these tools often use languages considered low level from the point of view of data scientists and are still much too difficult to use for software developers. This complexity limits their usage in a number of fields, from data science to signal processing, where the computational power offered by FPGAs could be highly beneficial. One way to overcome this problem is to realize libraries of widely used algorithms that transparently offload the computation to the FPGAs device from modern High Level Languages. Our work presents an interface between R, a language commonly used by statisticians and data scientists, and an FPGA connected via PCI-Express (PCIe). We use the Reusable Integration Framework for FPGA Accelerators (RIFFA) to send and receive data from PCIe connection. To showcase the use of the described interface and the improvements given by making use of FPGAs in signal analysis applications we used Xilinx Vivado Design Suite to implement an accelerated and optimized version of the Autocorrelation Function (ACF) present in the default libraries used by R
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