1,721,179 research outputs found
Recent Findings Confirm LIM Domain Kinases as Emerging Target Candidates for Cancer Therapy
No full textThe two members of the LIM domain kinase family (LIMK1 and LIMK2) represent crucial keys in the signaling pathways that modulate the structure and activity of actin cytoskeleton. They maintain the optimal balance between phosphorylated and unphosphorylated cofilin that in turn acts by severing filamentous actin into globular actin and ensures actin turnover and cytoskeleton regulation. Many macromolecular partners able to regulate LIMK activity (positive and negative regulators) do exist. Proteins that enhance or reduce the nucleocytoplasmic shuttling of LIMK by direct or indirect interaction are also known. Among many LIMK activators, members of the Rho family of small GTPases (i.e., Rho, Rac, and Cdc42) and their downstream effectors (i.e., ROCK, PAK, and MK2) are involved in the progression of various human cancers toward invasive and metastatic stages. As LIMK are centrally positioned in the pathways leading to cytoskeleton dynamics and regulation, they could be considered as valuable targets for actin regulation. Fine modulation of LIMK activity could be a major challenge to inhibit tumor cell invasion mediated by one or a combination of the upstream signaling factors. As LIMK play a critical role in tumor cell invasion, they may be candidate targets for developing novel therapeutic agents toward tumor invasion and metastasis
Prima lingua e identità: il caso della seconda generazione degli arabofoni in Italia
Full text linkQuesta ricerca si propone di delineare un quadro complessivo delle problematiche sociolinguistiche relative all’esperienza della seconda generazione di arabofoni in Italia e alla loro percezione del concetto di identità attraverso il legame con la lingua di origine. E ciò allo scopo di illustrare il valore che questa seconda generazione di arabofoni attribuisce alla lingua araba come marcatore di identità e di appartenenza culturale ed etnica. Questo studio mira inoltre ad analizzare le loro attitudini linguistiche, l’uso dell’arabo nella vita quotidiana e il loro bi-plurilinguismo, senza trascurare il legame della seconda generazione con il paese di origine, il ruolo della lingua araba nel mantenerlo vivo, nonché il ruolo dei genitori nella trasmissione della lingua e cultura araba ai propri figli e, infine, il grado di mantenimento / perdita dell’arabo nel contesto immigratorio. La ricerca si articola in due parti principali: una teorica, e la seconda è una ricerca sul campo per valutare il legame fra la lingua materna, e la costruzione identitaria delle seconde generazioni degli arabofoni nati in Italia o arrivati in età prescolare. Nella prima fase sono stati illustrati i risultati dell’analisi di ogni livello di istruzione in modo descrittivo. Nella fase successiva è stata applicata una ulteriore analisi incrociando i dati con tre variabili: Livello di istruzione che corrisponde alla fascia di età, Genere e il Paese di origine dei genitori. L’illustrazione dei risultati segue un ordine comune in base a quattro parametri socioculturali: attitudini linguistiche, il legame con il paese di origine, il grado di socializzazione e integrazione e il senso di appartenenza. Infine sono stati raccolti i risultati finali in base al senso di appartenenza e illustrati le caratteristiche sociolinguistiche dei tre profili identitari che emergono da questa ricerca (sentirsi italiano, sentirsi arabo, sentirsi italo-arabo)
Pharmacophoric models and 3D QSAR studies of the adenosine receptor ligands
No full textComputational methodologies are used to increase the efficiency of drug discovery process by rendering the design of new drug candidates more rapid and cost-efficient. In silico techniques can be divided in two main groups. Structure-based drug design procedures can be applied (such as docking simulations) if the target is known from experimental (i.e., X-ray crystallographic studies, NMR studies) or theoretical sources (receptor structure built by homology modeling techniques). Otherwise, ligand-based drug design methods can be used (e.g., QSAR or 3D QSAR models, pharmacophoric models) based on the analysis of a number of ligands known to act with a common mechanism of action. Adenosine receptors (ARs) are a family of G-protein coupled receptors (GPCRs) of great interest as targets for therapeutic intervention. Due partly to the lack of reliable adenosine receptor structures, ligand-based drug discovery methods remain the major computational molecular modeling approach applied in the research of new AR ligands. The scope of this review is to summarize the results on pharmacophoric models and 3D QSAR studies concerning AR ligands. In particular, the review will focus on the use of such ligand-based computational techniques for the identification of new AR ligands and/or for their optimization
New derivatives of BM 212, a class of antimycobacterial compounds based on the Pyrrole ring as a scaffold
No full textIn Memory of Maurizio Botta: His Contribution to the Development of Computer-Aided Drug Design
Full text linkMaurizio Botta was born in Manziana, near Rome (Italy), on May 1950. He built his background in chemistry at Sapienza University of Rome, and then, he received his Ph.D. in 1979 at the University of Brunswick (Canada) working at the total synthesis of complex natural products under the supervision of Prof. Karel Wiesner. From 1980 to 1987, he was a Researcher at the Sapienza University of Roma, and thanks to a NATO grant, he spent one year in 1985–1986 working as a postdoctoral associate in the group of Prof. Stephen Hanessian at the University of Montreal (Canada), where he was also invited as a visiting scientist many other times thereafter.(1) In 1987, he became an Associate Professor of medicinal chemistry at the University of Siena (Italy) and then a Full Professor in 2000. His scientific career was objectively successful, as he was author in more than 400 papers and books or book chapters, as well as inventor in more than 25 patents. He was a member of many scientific societies and editorial boards of journals mostly devoted to chemistry, medicinal chemistry and drug design. Particularly, he served as an Associate Editor for ACS Medicinal Chemistry Letters.
Besides his chemical background, in his research life Maurizio was intrigued by multiple fields adjacent to synthetic chemistry, such as biochemistry, biophysics, molecular biology, and computational modeling. This latter captured his attention and was implemented in his research activity as a crucial support to drug design since the beginning of the 1990s. It is worth noting that most of Botta’s publications report on the use of computational tools, mostly relying on (but not limited to) molecular mechanics (MM) approaches to rationalize existing biological data, or to drive the design and synthesis of bioactive compounds. His research initially focused on conformational analysis of small molecules with the double aim to seize the enormous possibilities offered by MM in modeling conformational flexibility detected by NMR spectroscopy, as well as to exploit the active analogue approach (AAA) developed by Prof. Garland Marshall to interpreting pharmacological properties of bioactive compounds.(2) Thanks to the fruitful collaboration with Prof. Kosta Steliou (University of Montreal), near the beginning of the 1990s, his group started to use the VAX version of Model software, implemented with the MMX force field that was especially suitable to modeling molecular systems with π-electron delocalization. In the same years, MacroModel was used to model with high accuracy the flexibility of an increased number of organic molecules thanks to different force fields, while the use of Sybyl was initially related to its graphic potential but would later pave the way to using the CoMFA 3D-QSAR methodology. Since then, the role of computational modeling studies became more and more relevant in the research of Maurizio’s group, up to the publication of papers mostly or exclusively conducted at the theoretical level. The crucial role of theoretical approaches in drug design was highlighted by the successful series of workshops, i.e., the European Workshop in Drug Design (EWDD), held every two years in the lovely location of Certosa di Pontignano in the countryside of Siena (Italy).
The aim of this paper is to honor the memory of Prof. Maurizio Botta and to briefly overview the major contributions he gave to the field of computer-aided drug design, chemical information, and modeling. Works that represented a milestone in his research strategy are briefly overviewed herein, grouped on the basis of the topic. Finally, a note to the EWDD series is provided
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
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Structural flexibility of hyaluronan oligomers as probed by molecular modeling
No full textIn the last few years, molecular modeling studies have been published that are devoted to a better understanding of the structural flexibility of hyaluronan (HA). Further conformational investigations, however, are needed on this polysaccharide, such as the application of statistical methods to perform enhanced one-step conformational analyses of its subunits. Moreover, the adjustment of assisted model building and energy refinement (AMBER) force field could provide the appropriate computational tool to study the interactions of HA and its derivatives with proteins. The present paper reports a combined Monte Carlo (MC) and molecular dynamics (MD) approach applied to the conformational study of HA, using an adjusted version of AMBER force field and the generalized Born solvent-accessible surface area (GB/SA) continuum solvation model. The MC approach turned out to be extremely effective to outline a conformational survey of the disaccharides constituting HA. Complete sets of conformations of the monomers were provided for the first time, some of which had never been predicted. MD technique, integrating the MC results, correctly reproduced the unusual stiffness of HA and predicted the existence of a minor skew-boat conformation of the β-D-glucuronic moiety. The computational approach, as a whole, improved the comprehension of the dynamic behavior of HA and offered a clear causal explanation of the relative dynamics of the glycosidic linkages
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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