1,721,014 research outputs found
A novel selective cell-permeable peptide disrupts presynaptic JNK2-STX1a interaction, providing neuroprotection and preventing glutamate-mediated excitotoxicity
Full text linkL-glutamate is the major excitatory neurotransmitter in the central nervous system of vertebrates. By playing a dual role as amino acid and neurotransmitter, glutamate fulfils a large array of physiological functions supporting neuronal development and cognitive performances. Consequently, the alteration of glutamate signaling entails profound detrimental effects that give rise to disease conditions, including excitotoxicity induced by cerebral ischemia.
Since plenty of reports have so far investigated the effects of cerebral ischemia at postsynaptic sites, little is known concerning the mechanisms activated by the ischemic injury at the presynaptic terminal.
NMDA receptors have been classically implicated in both postsynaptic and presynaptic pathways sustaining excitotoxicity, but only recently their intracellular association with the c-Jun N-terminal kinase (JNK) has also been involved in such pathological mechanisms.
Our previous findings already underlined a specific and unique involvement of the JNK2 isoform as a pivot player in glutamate release, when focusing on presynaptic sites. In the present dissertation we furthermore unveil the selective protein-protein interaction between JNK2 and Syntaxin-1a (STX1a), emphasizing their unexplored contribution in the docking and release of synaptic vesicles at the basis of the NMDA-evoked excitotoxicity. On purpose, we have developed JGRi1, a cell-permeable peptide able to selectively disrupt JNK2/STX1a interplay and pharmacologically prevent the downstream ischemic cascade. To uphold our hypothesis, we tested JGRi1 in several experimental settings, achieving a convincing neuroprotective effect also in a murine model of ischemia over a conveniently long therapeutic window. Conclusively, we analysed the presence of three single nucleotide polymorphisms (SNPs) on the STX1A gene in a cohort of stroke patients, evidencing a haplotype correlated with increased susceptibility to cerebral ischemia. Overall, we here confirm JNK fundamental implication in glutamate release at presynaptic level, moreover presenting for the first time JGRi1, a selective inhibitor of the JNK2/STX1a interaction that may represent a new therapeutic tool able to modulate glutamate overflow in various conditions, including neurodegenerative diseases and ischemia-linked pathologies
A loophole in the Eurocode 8 allowing for non-conservative seismic design
No full textThe prescriptions of the Eurocode 8 (EC8) concerning the static method of seismic analysis may lead to non-conservative design with respect to the more rigorous modal response spectrum analysis. The reason is the unconditioned reference the EC8 makes to the correct value of the fundamental period of vibration of the building. This can produce non-conservative results, especially when the method is applied to buildings that are not regular in plan. The present paper shows how this can happen by referring to the seismic analysis of a series of buildings with different eccentricities between center of mass and center of stiffness. The result should prompt appropriate changes to be introduced in the EC8. The paper also hints at some possible routes to avoid this shortcoming
Competing feedback in an idealized tide-influenced delta network
No full textThe morphodynamic evolution of river deltas is intimately tied to flow and sediment partitioning at bifurcations. In this work, the long-term equilibrium configuration of a simple delta network is investigated by means of an analytical model, which accounts for the effect of small tidal oscillations. Differently from individual bifurcations where tidal action is always a stabilizing factor, in the case of a tree-like delta with multiple bifurcations a dual response emerges. Specifically, depending on the values of four reference parameters functions of tidal amplitude, upstream flow conditions, and channels geometry, tides can either promote or discourage an unbalanced discharge distribution. This behavior primarily concerns the apex bifurcation, which is affected by the variations of the relative tidal amplitude at the internal nodes. In turn these variations depend on how flow and sediment are diverted upstream. The stability of steady-state solutions is found to be governed by the sign and magnitude of the slope asymmetry between channels. This work provides a basic modeling framework for the interpretation of the autogenic response of multiple coupled micro-tidal bifurcations, which can potentially be extended to include in a unified scheme erosional and depositional processes typical of fluvio-deltaic systems
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
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
Hydrostatic vs. non-hydrostatic modelling of density currents developing two dimensionally on steep and mild slopes
No full textSalinity and turbidity currents developing two dimensionally on steep and mild slopes are simulated numerically. An application of the process-based model Delft3D-Flow is presented that is able to capture the dynamics of subaqueous dense underflows by solving the two dimensional over the vertical (2DV) Reynolds-averaged Navier–Stokes equations under hydrostatic (H) and non-hydrostatic (NH) pressure assumptions. The development of conservative density currents that plunge in fresh water as a result of an upstream input of denser salty water and turbidity currents flowing down a fixed sandy bed with uniform slope are thoroughly investigated. Down-slope evolution of the modelled density currents is characterised by water entrainment coefficients that fall within the range of laboratory data. Vertical profiles of both velocity and excess density conform with previous experimental measurements. NH solutions, differently from their H counterparts, are shown to capture in detail time-dependent stages of dense undercurrents, such as the dynamics of their fronts, the passage of their heads as well as the development of Kelvin–Helmholtz (KH) instabilities at their interfaces with the ambient fluid resulting in the velocity pulsing of their bodies. Nonetheless, the H application of Delft3D-Flow predicts fairly well the steady state of salty and turbid undercurrents, thus representing a computationally cost-effective alternative for the modelling of field-scale density currents
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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