1,721,417 research outputs found
Indolylarylsulfones, a fascinating story of highly potent human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors
Full text linkIndolylarylsulfones are a potent class of human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitors. In this review, the structure activity relationship (SAR) studies to improve the profile of sulfone L-737,126 discovered by Merck AG have been analysed with focus on introduction of the 3',5'-dimethyl groups at the 3-phenylsulfonyl moiety, the 2-hydroxyethyl tail at the indole-2-carboxamide nitrogen, coupling of the carboxamide nitrogen with one or two glycinamide and alaninamide units, a fluorine atom at position 4 of the indole ring and correlation between configuration of the asymmetric centre and linker length. IAS derivatives look like promising drug candidates for the treatment of AIDS and related infections in combination with other antiretroviral agents
DNA polymerases in the risk and prognosis of colorectal and pancreatic cancers
Full text linkHuman cancers arise from the alteration of genes involved in important pathways that mainly affect cell growth and proliferation. DNA replication and DNA damages recognition and repair are among these pathways and DNA polymerases that take part in these processes are frequently involved in cancer onset and progression. For example, damaging alterations within the proofreading domain of replicative polymerases, often reported in patients affected by colorectal cancer (CRC), are considered risk factors and drivers of carcinogenesis as they can lead to the accumulation of several mutations throughout the genome. Thus, replicative polymerases can be involved in cancer when losses of their physiological functions occur. On the contrary, reparative polymerases are often involved in cancer precisely because of their physiological role. In fact, their ability to repair and bypass DNA damages, which confers genome stability, can also counteract the effect of most anticancer drugs. In addition, the altered expression can characterise some type of cancers, which exacerbates this aspect. For example, all of the DNA polymerases involved a damage bypass mechanism, known as translesion synthesis, with the only exception of polymerase theta, are downregulated in CRC. Conversely, in pancreatic ductal adenocarcinoma (PDAC), most of these polymerase result upregulated. This suggests that different types of cancer can rely on different reparative polymerases to acquire drug resistance. Here we will examine all of the aspects that link DNA polymerases with CRC and PDAC
Parsimonious Flooding in Geometric Random-Walks∗
No full textWe study the information spreading yielded by the \emph{(Parsimonious) 1-Flooding Protocol} in geometric Mobile Ad-Hoc Networks. We consider n agents on a convex plane region of diameter D performing independent random walks with move radius ρ. At any time step, every active agent v informs every non-informed agent which is within distance R from v (R>0 is the transmission radius). An agent is only active at the time step immediately after the one in which has been informed and, after that, she is removed. At the initial time step, a source agent is informed and we look at the \emph{completion time} of the protocol, i.e., the first time step (if any) in which all agents are informed. This random process is equivalent to the well-known \emph{Susceptible-Infective-Removed (SIR}) infection process in Mathematical Epidemiology. No analytical results are available for this random process over any explicit mobility model. The presence of removed agents makes this process much more complex than the (standard) flooding. We prove optimal bounds on the completion time depending on the parameters n, D, R, and ρ. The obtained bounds hold with high probability. We remark that our method of analysis provides a clear picture of the dynamic shape of the information spreading (or infection wave) over the time
Small molecule inhibitors of kdm5 histone demethylases increase the radiosensitivity of breast cancer cells overexpressing JARID1B
No full textNHERF1 (Na+/H+ exchanger 3 regulating factor 1) is an integral membrane adaptor protein carrying two NH2-terminal PDZ (postsynaptic density 95/discs large/zona occludens 1) tandem domains.1 PDZ1 (11-97 amino acids) and PDZ2 (150-237 amino acids) show 74% identity to each other and bind to specific carboxyl-terminal motifs on target proteins, such as -catenin and PTEN, that may have a pivotal role in tumorigenesis. Oncogenic activity of NHERF1 is strictly dictated by changes on its subcellular localization.1,2 A pharmacophore model was used to filter out an in-house training set of about 6000 compounds, leading to identify a potent inhibitor of NHERF1.3 We herein reported the design and synthesis of new NHERF1 inhibitors (Figure 1).4 The new compounds were synthesized by treating the appropriate indole with thionyl chloride and the proper amino derivative in the presence of pyridine in dichloromethane at room temperature for 12 h; alternatively, the coupling reaction was carried out using (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate and triethylamine in N,N-dimethylformamide at room temperature for 12 h. Compounds 5, 9, 10 and 13 exhibited a remarkable cytotoxicity in Ls174TshBeta-Cat cells. The binding to NHERF1 PDZ was confirmed by means of a dansylated peptide corresponding to the C-terminal sequence of Beta2-AR. When used in combination with antagonists of Beta-catenin, the new derivatives increased the apoptotic death of colorectal cancer cells refractory to currently available Wnt/Beta-catenin-targeted agents. References 1. Vaquero, J.; Nguyen Ho-Bouldoires, T. H.; Clapéron, A.; Fouassier, L. Oncogene 2017, 36, 3067‒3079. 2. Georgescu, M. M.; Morales, F. C.; Molina, J. R.; Hayashi, Y. Curr. Mol. Med. 2008, 8, 459−468. 3. Saponaro, C.; Sergio, S.; Coluccia, A.; De Luca, M.; La Regina, G.; Mologni, L.; Famiglini, V.; Naccarato, V.; Bonetti, D.; Gautier, C.; Gianni, S.; Vergara, D.; Salzet, M.; Fournier, I.; Bucci, C.; Silvestri, R.; Gambacorti Passerini, C.; Maffia, M.; Coluccia, A. M. L. Oncogene 2018, 37, 3301‒3316. 4. Coluccia, A.; La Regina, G.; Naccarato, V.; Nalli, M.; Orlando, V.; Biagioni, S.; De Angelis, M. L.; Baiocchi, M.; Gautier, C.; Gianni, S.; Di Pastena, F.; Di Magno, L.; Canettieri, G.; Coluccia, A. M. L.; Silvestri, R. ACS Med. Chem. Lett. 2019, 10, 499‒503
Broadcasting in Dynamic Radio Networks
Full text linkIt is reasonable to claim that almost all major questions related to radio broadcasting can be considered closed as far as static networks are considered: the network never changes during the entire protocol's execution. On the other hand, theoretical results on communication protocols in any scenario where the network topology may change during protocol's execution (i.e. a dynamic radio network) are very few.
In this paper, we present a theoretical study of broadcasting in radio networks having dynamic unknown topology. The dynamic network is modeled by means of adversaries: we consider two of them. We first analyze an oblivious, memoryless random adversary that can be seen as the dynamic version of the average-case study presented by Elsässer and Gasieniec in JCSS, 2006. We then consider the deterministic worst-case adversary that, at each time slot, can make any network change (thus the strongest adversary). This is the dynamic version of the worst-case study provided by Bar-Yehuda, Goldreich and Itai in JCSS, 1992.
In both cases we provide tight bounds on the completion time of randomized broadcast protocols
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
ICT ed innovazione nell’agroalimentare: indagine empirica sulle imprese del comparto dell’olio extravergine d’oliva da agricoltura biologica
No full textAbstract
Obiettivi. Si indaga il comportamento gestionale effettivo delle imprese agroalimentari di un comparto tradizionale specifico, l’olio extra vergine d’oliva, che hanno innovato i metodi di produzione verso la sostenibilità ambientale (agricoltura biologica), per verificare le eventuali scelte innovative di creazione di valore basate sull’impiego delle tecnologie digitali e del web.
Metodologia. L’indagine è esplorativa e di carattere segnaletico, con analisi cluster dei dati, raccolti mediante somministrazione di un questionario, tramite l’applicazione Google Docs, ad un panel di produttori di olio extravergine d’oliva biologico, estratto dall’intero campione di aziende partecipanti al Premio Internazionale Biol.
Risultati. Si rileva se e come il comportamento effettivo di un segmento d’imprese tradizionali agroalimentari, faccia leva su modalità gestionali innovative basate su internet e sulle ICT.
Limiti della ricerca. L’indagine esplorativa, di carattere essenzialmente segnaletico, è effettuata su un campione di imprese la cui dimensione e le cui caratteristiche specifiche non consentono delle generalizzazioni teoriche, ma permettono esclusivamente delle considerazioni segnaletiche degli attuali concreti orientamenti gestionali attuati da imprese tradizionali.
Implicazioni pratiche. Possibile individuazione di nuovi orientamenti gestionali innovativi, che consentano alle imprese agroalimentari minori di sfruttare in pieno le potenzialità dell’innovazione di prodotto (olio extravergine d’oliva biologico) e della rete web (Internet ed e-commerce).
Originalità del lavoro. L’indagine è condotta su un panel internazionale d’imprese, operanti in un comparto specifico del settore agroalimentare, ed evidenzia l’attuale effettiva propensione all’innovazione gestionale basata sulle ICT
La gestione del rischio: strumenti pubblici e privati in Ragionando di Sviluppo locale: una lettura “nuova” di tematiche “antiche”
No full textL’impresa è un sistema aperto che vive e agisce all’interno di un dedalo molto più ampio di relazioni con altri operatori economici dal cui intreccio si delinea una stratificazione di sistemi (finanziario, operativo, delle forni-ture, distributivo, ecc.) in condizione di sovra o subordinazione reciproca, finalizzati alla creazione e ottimale allocazione del valore fra tutte le parti
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