a decoupled numerical procedure for modelling soil interaction in the computation of the dynamic response of a rail track

Abstract The problem of vibration transmitted by train traffic to the soil in the case of railway lines in urban areas is gaining increasing attention in environmental impact analysis. An efficient method to consider both the train-track interaction in detail and the vibration transmitted to the soil nearby with an affordable computational cost is desirable. The paper proposes a numerical procedure based on a substructuring approach, in which the system is divided into three main subdomains: the train running on the track, the rail subjected to the loads coming from the train and the reactions from the sleepers and the "ground" sub-system, composed by the sleepers, the ballast with its subgrade and the actual ground. The overall procedure is divided into subsequent steps: first, the finite element modelling of the sleeper-ballast-subgrade combined system, characterized within the linear elastic field by means of frequency response functions at rail-sleeper interfaces. In a second step, moving loads transmitted to the track are computed by numerical time domain integration of the equations of motion of the train running on a model of the track only, in which the subgrade is modelled as a series of spring-damper elements, whose parameters are tuned according to the results of the FE model used in the first step and therefore consistent with it. Non-linear behavior of the rail-wheel interaction can be accounted for by the time-domain procedure. The track dynamics is finally computed via direct frequency domain analysis; the track is again modelled by Finite Elements, loaded by the forces transmitted by the train wheels and by the supporting sleepers. Finally, the vibrations propagated through the soil to a general receiver point are evaluated. The procedure can exploit favorable properties of frequency domain analysis in treating moving loads; in addition, frequency dependent properties of materials can be introduced

Syllabic effects in Italian lexical access

Two cross-modal priming experiments tested whether lexical access is constrained by syllabic structure in Italian. Results extend the available Italian data on the processing of stressed syllables showing that syllabic information restricts the set of candidates to those structurally consistent with the intended word (Experiment 1). Lexical access, however, takes place as soon as possible and it is not delayed till the incoming input corresponds to the first syllable of the word. And, the initial activated set includes candidates whose syllabic structure does not match the intended word (Experiment 2). The present data challenge the early hypothesis that in Romance languages syllables are the units for lexical access during spoken word recognition. The implications of the results for our understanding of the role of syllabic information in language processing are discussed

Large Deviation Approach to the Randomly Forced Navier-Stokes Equation

The random forced Navier-Stokes equation can be obtained as a variational problem of a proper action. By virtue of incompressibility, the integration over transverse components of the fields allows to cast the action in the form of a large deviation functional. Since the hydrodynamic operator is nonlinear, the functional integral yielding the statistics of fluctuations can be practically computed by linearizing around a physical solution of the hydrodynamic equation. We show that this procedure yields the dimensional scaling predicted by K41 theory at the lowest perturbative order, where the perturbation parameter is the inverse Reynolds number. Moreover, an explicit expression of the prefactor of the scaling law is obtained.Comment: 24 page

Double-Stranded RNA Targeting Dicer-Like Genes Compromises the Pathogenicity of Plasmopara viticola on Grapevine

Downy mildew caused by Plasmopara viticola is one of the most devastating diseases of grapevine, attacking all green parts of the plant. The damage is severe when the infection at flowering stage is left uncontrolled. P. viticola management consumes a significant amount of classical pesticides applied in vineyards, requiring efficient and environmentally safe disease management options. Spray-induced gene silencing (SIGS), through the application of exogenous double-stranded RNA (dsRNA), has shown promising results for the management of diseases in crops. Here, we developed and tested the potential of dsRNA targeting P. viticola Dicer-like (DCL) genes for SIGS-based crop protection strategy. The exogenous application of PvDCL1/2 dsRNA, a chimera of PvDCL1 and PvDCL2, highly affected the virulence of P. viticola. The reduced expression level of PvDCL1 and PvDCL2 transcripts in infected leaves, treated with PvDCL1/2 dsRNA, was an indication of an active RNA interference mechanism inside the pathogen to compromise its virulence. Besides the protective property, the PvDCL1/2 dsRNA also exhibited a curative role by reducing the disease progress rate of already established infection. Our data provide a promising future for PvDCL1/2 dsRNA as a new generation of RNA-based resistant plants or RNA-based agrochemical for the management of downy mildew disease in grapevine

Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR-32a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR-32a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose-based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H-NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR-32a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains

Insight into GEBR\u201032a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

Alzheimer\u2019s disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well\u2010established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE). In recent years, GEBR\u201032a has been shown to possess selective inhibitory properties against PDE type 4 family members, resulting in an improvement in spatial memory processes without the typical side effects that are usually correlated with this mechanism of action. In this work, we performed the HPLC chiral resolution and absolute configuration assignment of GEBR\u201032a. We developed an efficient analytical and semipreparative chromatographic method exploiting an amylose\u2010based stationary phase, we studied the chiroptical properties of both enantiomers and we assigned their absolute configuration by 1H\u2010NMR (nuclear magnetic resonance). Lastly, we measured the IC50 values of both enantiomers against both the PDE4D catalytic domain and the long PDE4D3 isoform. Results strongly support the notion that GEBR\u201032a inhibits the PDE4D enzyme by interacting with both the catalytic pocket and the regulatory domains

Morphometric analysis of astrocytes in brainstem respiratory regions

Astrocytes, the most abundant and structurally complex glial cells of the central nervous system, are proposed to play an important role in modulating the activities of neuronal networks, including respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) located in the ventrolateral medulla of the brainstem. However, structural properties of astrocytes residing within different brainstem regions are unknown. In this study astrocytes in the preBötC, an intermediate reticular formation (IRF) region with respiratory-related function, and a region of the nucleus tractus solitarius (NTS) in adult rats were reconstructed and their morphological features were compared. Detailed morphological analysis revealed that preBötC astrocytes are structurally more complex than those residing within the functionally distinct neighboring IRF region, or the NTS, located at the dorsal aspect of the medulla oblongata. Structural analyses of the brainstem microvasculature indicated no significant regional differences in vascular properties. We hypothesize that high morphological complexity of preBötC astrocytes reflects their functional role in providing structural/metabolic support and modulation of the key neuronal circuits essential for breathing, as well as constraints imposed by arrangements of associated neurons and/or other local structural features of the brainstem parenchyma

Novel compounds targeting the RNA-binding protein HuR : Structure-based design, synthesis and interaction studies

The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies (i.e., cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Nevertheless, medicinal-chemistry efforts aimed at developing such compounds are still at an early stage. As part of our ongoing research in this field, we hereby present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR-RNA interferers. The following assessment of the structural features of their interaction with HuR, combining saturation-transfer difference NMR and in silico studies, provides a guide for further research on the development of new effective interfering compounds of the HuR-RNA complex

Anti-tumor efficacy assessment of the sigma receptor pan modulator RC-106. A promising therapeutic tool for pancreatic cancer

Introduction: Pancreatic cancer (PC) is one of the most lethal tumor worldwide, with no prognosis improvement over the past 20-years. The silent progressive nature of this neoplasia hampers the early diagnosis, and the surgical resection of the tumor, thus chemotherapy remains the only available therapeutic option. Sigma receptors (SRs) are a class of receptors proposed as new cancer therapeutic targets due to their over-expression in tumor cells and their involvement in cancer biology. The main localization of these receptors strongly suggests their potential role in ER unfolded protein response (ER-UPR), a condition frequently occurring in several pathological settings, including cancer. Our group has recently identified RC-106, a novel pan-SR modulator with good in vitro antiproliferative activities toward a panel of different cancer cell lines. In the present study, we investigated the in vitro properties and pharmacological profile of RC-106 in PC cell lines with the aim to identify a potential lead candidate for the treatment of this tumor. Methods: Pancreatic cancer cell lines Panc-1, Capan-1, and Capan-2 have been used in all experiments. S1R and TMEM97/S2R expression in PC cell lines was quantified by Real-Time qRT-PCR and Western Blot experiments. MTS assay was used to assess the antiproliferative effect of RC-106. The apoptotic properties of RC-106 was evaluated by TUNEL and caspase activation assays. GRP78/BiP, ATF4, and CHOP was quantified to evaluate ER-UPR. Proteasome activity was investigated by a specific fluorescent-based assay. Scratch wound healing assay was used to asses RC-106 effect on cell migration. In addition, we delineated the in vivo pharmacokinetic profile and pancreas distribution of RC-106 in male CD-1 mice. Results: Panc-1, Capan-1, and Capan-2 express both SRs. RC-106 exerts an antiproliferative and pro-apoptotic effect in all examined cell lines. Cells exposure to RC-106 induces the increase of the expression of ER-UPR related proteins, and the inhibition of proteasome activity. Moreover, RC-106 is able to decrease PC cell lines motility. The in vivo results show that RC-106 is more concentrated in pancreas than plasma. Conclusion: Overall, our data evidenced that the pan-SR modulator RC-106 is an optimal candidate for in vivo studies in animal models of PC