872 research outputs found

    Stem-like and highly invasive prostate cancer cells expressing CD44v8-10 marker originate from CD44-negative cells

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    In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44neg). Unexpectedly, these sorted CD44neg cells rapidly and spontaneously converted to a stable CD44high phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44high subpopulation failed to express. Surprisingly and potentially interesting, in these cells expression of CD44v8-10 was found to be induced in stem cell medium. CD44 variant isoforms are known to be more expressed in CSC and metastatic cells than CD44 standard isoform. In agreement, functional analysis of the two sorted and cultured subpopulations has shown that the CD44v8-10pos PC3 cells, resulting from the conversion of the CD44neg subpopulation, were more invasive in vitro and had a higher clonogenic potential than the sorted CD44high cells, in that they produced mainly holoclones, known to be enriched in stem-like cells. Of interest, the CD44v8-10 is more expressed in human PCa biopsies than in normal gland. The discovery of CD44v8-10pos cells with stem-like and invasive features, derived from a minoritarian CD44neg cell population in PCa, alerts on the high plasticity of stem-like markers and urges for prudency on the approaches to targeting the putative CSC

    Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics.

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    Recent studies have indicated that the serotonin receptor subtype 7 (5-HT7R) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life. Here we show that pharmacological stimulation of 5-HT7R using a highly selective agonist, LP-211, enhances neurite outgrowth in neuronal primary cultures from the cortex, hippocampus and striatal complex of embryonic mouse brain, through multiple signal transduction pathways. All these signaling systems, involving mTOR, the Rho GTPase Cdc42, Cdk5, and ERK, are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth. Indeed, our data indicate that neurite elongation stimulated by 5-HT7R is modulated by drugs affecting actin polymerization. In addition, we show, by 2D Western blot analyses, that treatment of neuronal cultures with LP-211 alters the expression profile of cofilin, an actin binding protein involved in microfilaments dynamics. Furthermore, by using microfluidic chambers that physically separate axons from the soma and dendrites, we demonstrate that agonist-dependent activation of 5-HT7R stimulates axonal elongation. Our results identify for the first time several signal transduction pathways, activated by stimulation of 5-HT7R, that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation. Therefore, the activation of 5-HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development

    Discovering universal statistical laws of complex networks

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    Different network models have been suggested for the topology underlying complex interactions in natural systems. These models are aimed at replicating specific statistical features encountered in real-world networks. However, it is rarely considered to which degree the results obtained for one particular network class can be extrapolated to real-world networks. We address this issue by comparing different classical and more recently developed network models with respect to their generalisation power, which we identify with large structural variability and absence of constraints imposed by the construction scheme. After having identified the most variable networks, we address the issue of which constraints are common to all network classes and are thus suitable candidates for being generic statistical laws of complex networks. In fact, we find that generic, not model-related dependencies between different network characteristics do exist. This allows, for instance, to infer global features from local ones using regression models trained on networks with high generalisation power. Our results confirm and extend previous findings regarding the synchronisation properties of neural networks. Our method seems especially relevant for large networks, which are difficult to map completely, like the neural networks in the brain. The structure of such large networks cannot be fully sampled with the present technology. Our approach provides a method to estimate global properties of under-sampled networks with good approximation. Finally, we demonstrate on three different data sets (C. elegans' neuronal network, R. prowazekii's metabolic network, and a network of synonyms extracted from Roget's Thesaurus) that real-world networks have statistical relations compatible with those obtained using regression models

    Shunting operations at flat yards : retrieving freight railcars from storage tracks

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    In this paper, we study the railcar retrieval problem (RRT) where specified numbers of certain types of railcars have to be withdrawn from the storage tracks of a flat yard. This task arises in the daily operations of workshop yards for railcar maintenance. The objective is to minimize the total cost of shunting via methods such as minimizing the usage of shunting engines. We describe the RRT formally, present a mixed-integer program formulation, and prove the general case to be NP-hard. For some special cases, exact algorithms with polynomial runtimes are proposed. We also analyze several intuitive heuristic solution approaches motivated by observed real-world planning routines. We evaluate their average performances in simulations with different scenarios and provide their worst-case performance guarantee. We show that although the analyzed heuristics result in much better solutions than the naive planning approach, they are still on average 30%-50% from the optimal objective value and may result in up to 14 times higher costs in the worst case. Therefore, we conclude that optimization should be implemented in practice in order to save valuable resources. Furthermore, we analyze the impacts of yard layout and the widespread organizational routine of presorting on the railcar retrieval cost

    La sinistra:italiana una commedia in tre atti.

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    L’entrata nella seconda Repubblica è stata scandita dalla marcia trionfale della sinistra in predicato di vincere le elezioni politiche. I risultati elettorali più gratificanti della sinistra sono stati la traballante vittoria del 1996 e le non vittorie (sostanziali pareggi) del 2006 e del 2013, al contrario erano certe nelle previsioni e nei fatti le vittorie berlusconiane del 2001 e del 2008

    Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis

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    Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions

    The Impact of the Unstructured Contacts Component in Influenza Pandemic Modeling

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    Individual based models have become a valuable tool for modeling the spatiotemporal dynamics of epidemics, e.g. influenza pandemic, and for evaluating the effectiveness of intervention strategies. While specific contacts among individuals into diverse environments (family, school/workplace) can be modeled in a standard way by employing available socio-demographic data, all the other (unstructured) contacts can be dealt with by adopting very different approaches. This can be achieved for instance by employing distance-based models or by choosing unstructured contacts in the local communities or by employing commuting data.Here we show how diverse choices can lead to different model outputs and thus to a different evaluation of the effectiveness of the containment/mitigation strategies. Sensitivity analysis has been conducted for different values of the first generation index G(0), which is the average number of secondary infections generated by the first infectious individual in a completely susceptible population and by varying the seeding municipality. Among the different considered models, attack rate ranges from 19.1% to 25.7% for G(0) = 1.1, from 47.8% to 50.7% for G(0) = 1.4 and from 62.4% to 67.8% for G(0) = 1.7. Differences of about 15 to 20 days in the peak day have been observed. As regards spatial diffusion, a difference of about 100 days to cover 200 km for different values of G(0) has been observed.To reduce uncertainty in the models it is thus important to employ data, which start being available, on contacts on neglected but important activities (leisure time, sport mall, restaurants, etc.) and time-use data for improving the characterization of the unstructured contacts. Moreover, all the possible effects of different assumptions should be considered for taking public health decisions: not only sensitivity analysis to various model parameters should be performed, but intervention options should be based on the analysis and comparison of different modeling choices

    Solitary fibrous tumor of the male breast: a case report and review of the literature

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    Extrapleural solitary fibrous tumors are very rare and occasionally they appear in extraserosal soft tissues or parenchymatous organs. In such cases the right preoperative diagnosis is often difficult and challenging, because both radiological and cytological examinations are not exhaustive. For these reasons, surgical excision is frequently the only way to reach the correct diagnosis and to achieve definitive treatment. A few cases of solitary fibrous tumors have been also described in the breast. Although rare, this lesion opens difficulties in preoperative diagnosis entering in differential diagnosis with other benign lesions as well as with breast cancer. In this article we describe a case of a solitary fibrous tumor of the breast in a 49-year-old man. Problems related to differential diagnosis and the possible pitfalls that can be encountered in the diagnostic iter of such rare tumor are discussed

    A New Method for the Characterization of Strain-Specific Conformational Stability of Protease-Sensitive and Protease-Resistant PrPSc

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    Although proteinacious in nature, prions exist as strains with specific self-perpetuating biological properties. Prion strains are thought to be associated with different conformers of PrPSc, a disease-associated isoform of the host-encoded cellular protein (PrPC). Molecular strain typing approaches have been developed which rely on the characterization of protease-resistant PrPSc. However, PrPSc is composed not only of protease-resistant but also of protease-sensitive isoforms. The aim of this work was to develop a protocol for the molecular characterization of both, protease-resistant and protease-sensitive PrPSc aggregates. We first set up experimental conditions which allowed the most advantageous separation of PrPC and PrPSc by means of differential centrifugation. The conformational solubility and stability assay (CSSA) was then developed by measuring PrPSc solubility as a function of increased exposure to GdnHCl. Brain homogenates from voles infected with human and sheep prion isolates were analysed by CSSA and showed strain-specific conformational stabilities, with mean [GdnHCl]1/2 values ranging from 1.6 M for MM2 sCJD to 2.1 for scrapie and to 2.8 M for MM1/MV1 sCJD and E200K gCJD. Interestingly, the rank order of [GdnHCl]1/2 values observed in the human and sheep isolates used as inocula closely matched those found following transmission in voles, being MM1 sCJD the most resistant (3.3 M), followed by sheep scrapie (2.2 M) and by MM2 sCJD (1.6 M). In order to test the ability of CSSA to characterise protease-sensitive PrPSc, we analysed sheep isolates of Nor98 and compared them to classical scrapie isolates. In Nor98, insoluble PrPSc aggregates were mainly protease-sensitive and showed a conformational stability much lower than in classical scrapie. Our results show that CSSA is able to reveal strain-specified PrPSc conformational stabilities of protease-resistant and protease-sensitive PrPSc and that it is a valuable tool for strain typing in natural hosts, such as humans and sheep

    Spike timing in rat somatosensory cortex contributes to behavior

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    The precise spike timing of sensory neurons carries more information about stimuli than the number of spikes counted over longer time windows [1-3]. However, the behavioral relevance of this extra information remains to be assessed. To investigate whether precise timing contributes to behavior, we considered spike trains recorded extracellularly in the rat somatosensory cortex during a texture discrimination task [4,5]. We analyzed the spike trains following the contact of the whiskers with the texture and we measured the information carried about texture by post-touch spike times and spike counts. This analysis is technical challenging because it is difficult to quantify the information content of precise patterns of spike that extend over relatively long time windows with the relatively little number of trials available in behavioral experiments. To address this challenge, we reduced the dimensionality of the response space by decomposing single trial spike train densities into Principal Components (PCs), selecting the most informative PC as the "temporal template" to interpret neural responses, and finally measuring the information about the presented texture carried by the projection of each trial relative to this template. We compared the so -measured spike timing information with the information carried by spike counts and we found that spike times carried more than 60% more texture information than spike counts. Next, we reasoned that if a neuronal coding mechanism contributes to behavior, then the code would be found to transmit less stimulus information in error trials, i.e. trials in which the rat made the wrong choice. We found that the texture information carried both by spike counts and spike patterns decreased significantly when we included error trials in the analysis, but the effect was much more pronounced for patterns (30% information decrease) than for counts (~15% information decrease). These differences between spike pattern and spike count codes hold for both primary and secondary somatosensory cortex, suggesting that spike timing could contribute to behavior at different stages of the sensory processing. Taken together, these results indicate that in the somatosensory cortex the time at which spikes occur, not just the number of spikes, makes a crucial contribution to tactile perception
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