1,721,287 research outputs found
Evaluation of operating speed for two-lane rural roads: an Italian case study
No full textThere are already many studies that have as their objective the evaluation of the environmental speed on tangent elements. in this paper we present a first solution to the problem of evaluation of environmental speed through the rural roads of the Province of Pisa. In the following, an overview is presented on the state of the art and on the existing models; in the second part is than presented the methodology followed for selection, data collection, calibration and validation of the model for the evaluation of an environmental speed on tangent elements, relating only to two-lane rural roads
AI3SD Video: Finding new in silico-based therapeutic strategies for IAHSP
No full textInfantile-onset ascending spastic paralysis (IAHSP) is a neurodegenerative autosomic recessive rare disease which affects less than 50 people worldwide. The pathogenesis starts in early childhood, with a progressive degeneration of the upper spinal motoneuron, progressively hindering deambulation until spread to the upper limbs and to the involuntary musculature(1). As it often occurs for rare diseases, although few interest from the pharma compartment, some information regarding this condition are available from case reports: key events responsible for this condition are mutations to the gene ALS2, which encodes for the cell trafficking-related protein alsin. Nevertheless, the relatively broad mutational landscape and the low number of reported cases still make a complete understanding of the physiopathology and the search for suitable therapeutic strategies pretty challenging. The majority of mutations described in literature result in a truncated form of alsin which is reputed to be degraded, thus depicting a scenario of loss-of-function pathogenesis. Nevertheless, some patients report missense mutation, leading to non-degraded, mutated forms. In those cases, the majority of amino-acid (aa) substitutions occur in the N-terminal RLD domain, essential for alsin localization to the plasma membrane and eventually to early and late endosomes upon activation of the RAC1 pathway. In endosomes, alsin binds to the small GTPase Rab5 and performs a guanosin-exchange factor activity (GEF) through its C-terminal VPS9 domain2. This pathway is reputed to be the major strategy that mammalian cells follow, in order to assemble endosomes and exchange materials within the cell architecture. In dimensionally important cells such as motoneurons, coordinated and efficient cell trafficking results crucial for correct development and function maintenance. Alsin exists in cytoplasmic solution as tetramer, firstly assembled by parallel dimerization through the VPS9 domain and subsequently by interaction of two dimers through their DH/PH domain, located upwards of the VPS9 region2. The first challenge that such a broad mutational landscape offers is that different mutations correspond to different multimers. These states do not just affect stability and solubility, but also subcellular localization and GEF activity. To make this situation more challenging, there is no experimentally-resolved 3D structure of alsin and a homology modeling effort to build the whole protein seems questionable because of the lack of a reliable template. In contrast with the majority of reports, here we present a patient case harboring two alsin mutations in the C-terminal region: one allele translates a frame-shifted, truncated form which gets degraded. The other allele is harboring the R1611W aa substitution in the VPS9 domain. With the aid of in silico computational tools, we managed to predict the 3D structure of normal and mutated forms of this domain. Moreover, we characterized physiologic and pathologic dimerization modes, discovering that mutated VPS9 preferentially forms an antiparallel dimer by interacting with the aforementioned RLD domain. We could link this discovery to the experimentally-determined loss of tetrameric aggregation and, more important, to the incorrect endosome localization. This finding corroborates and gives a mechanistic explanation for the experimentally-characterized reduced Rab5 GEF endosomal activity. Furthermore, we performed an in silico virtual screening, repurposing an already commercialized drug which is able to shield the pathologically-acquired hydrophobic moiety. In our hypothesis, this mechanism of action re-establishes physiological dimerization mode, subcellular localization and Rab5 activity in R1611W-mutated patients. The candidate is currently under pre-clinical testing in an alsin R1611W cellular model. Our hope and the scope of our effort is duplex: first, we want to provide a reliable treatment for alleviating symptoms and disease progression to our patient. Second, we would like to broaden the knowledge in the field and, by integrating in silico and in vitro procedures, establish a lean research pipeline that might once serve as mutation-based platform for individual drug repurposing for the treatment of alsin-related diseases.References:Lesca, G. et al. Infantile ascending hereditary spastic paralysis (IAHSP): Clinical features in 11 families. Neurology 60, 674–682 (2003).Sato, K. et al. Altered oligomeric states in pathogenic ALS2 variants associated with juvenile motor neuron diseases cause loss of ALS2-mediated endosomal function. J. Biol. Chem. 293, 17135–17153 (2018)
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
ELEMENTI FONDAMENTALI PER REDIGERE UN PIANO DEL TRAFFICO PER LA VIABILITA’ EXTRAURBANA
No full textSommario - Oggi più che mai è necessario affrontare il problema delle reti stradali di rilevanza nazionale attraverso il miglioramento dell’efficienza e della sicurezza di circolazione delle infrastrutture già esistenti. Già il Nuovo Codice della Strada, emanato nell’ormai lontano 1992, conteneva (art. 36) indicazioni in merito all’adozione di strumenti pianificatori dedicati a questi ambiti, quali i Piani Urbani del Traffico (PUT) e i Piani del Traffico per la Viabilità Extraurbana (PTVE). Nel rispetto dei fini di tali strumenti, così come indicati dallo stesso NCdS, (il miglioramento delle condizioni di circolazione e della sicurezza stradale, la riduzione degli inquinamenti acustico ed atmosferico ed il risparmio energetico), con il presente lavoro si è inteso affrontare alcuni degli elementi ritenuti imprescindibili per la redazione di Piani per la Viabilità Extraurbana (la classificazione delle strade esistenti, la stima delle velocità sia operative che assimilabili a quelle di progetto, analisi e valutazione del rischio connesso a vari aspetti inerenti la sicurezza stradale e altro). Ciascuno di essi è stato trattato separatamente ed approfonditamente per giungere alla messa a punto di strumenti originali per il calcolo e l’applicazione, intendendo in questo modo rendere disponibili veri e propri strumenti applicativi che fungano da guida per la stesura degli stessi PTVE, oltre che per la pianificazione delle azioni da includere al loro interno
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
Raised crosswalks and their design features in traffic calming
Full text linkA road hump, or speed hump, is a traffic calming device used to reduce vehicle speed and volume on residential streets. Road humps are placed across the road to slow traffic and are often installed in a series of several humps in order to prevent cars from speeding before and after the hump. Speed humps are used in locations where very low speeds are desired and reasonable. Speed humps are typically placed on residential roads and are not used on major roads, bus routes, or primary emergency response routes. In Italy, the road humps are often built in shape of raised crosswalks, or RCWs, and they are generally placed both close and between intersections.
This paper deals with the analysis of observed data on a large sample of RCWs located in Tuscany, central Italy. Such data were referred both to geometry characteristics of the single raised crosswalk and recorded differences in vehicle speeds before and after it. Speed data were gathered using two automatic radar-recorders for each one of the sampled raised crosswalks.
All the collected data were analyzed trough statistical tests in order to assess their homogeneity or not between different locations and various types of roads. Finally, we were able of making some conclusions and highlighting design aspects. On one side, RCWs with similar geometries and higher heights (about 15 cm) have similar effects on vehicle speeds lowering, regardless of local conditions (location, road geometry, driver behaviour, etc.).
Moreover, raised crosswalks installed in a series have strong efficacy than the isolated ones. On the opposite side, the effects of raised crosswalks with smaller heights (less than 6 cm) show clearly a very low influence on vehicle speed variations
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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