Parabolic Orbits in the Elliptic Restricted Three Body Problem

AbstractThe main goal of this paper is to describe the parabolic orbits of the planar restricted elliptic three body problem. The method used is based on a standard blow up of the periodic orbits at the infinity and the perturbation of the integrable case corresponding to mass parameter equal to zero. We give an asymptotic formula for the distance between the stable and unstable manifolds of the infinity which allows us to describe how the heteroclinic orbits are created, changing the eccentricity of the primaries. Some conclusions of the quantitative study are given at the end

Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials

The clinical utility of serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC) is widely recognised. However, a clear understanding of the mechanisms of AFP overexpression and the molecular traits of patients with AFP-high tumours are not known. We assessed transcriptome data, whole-exome sequencing data and DNA methylome profiling of 520 HCC patients from two independent cohorts to identify distinct molecular traits of patients with AFP-high tumours (serum concentration?>?400?ng/ml), which represents an accepted prognostic cut-off and a predictor of response to ramucirumab. Those AFP-high tumours (18% of resected cases) were characterised by significantly lower AFP promoter methylation (p?<?0.001), significant enrichment of progenitor-cell features (CK19, EPCAM), higher incidence of BAP1 oncogene mutations (8.5% vs 1.6%) and lower mutational rates of CTNNB1 (14% vs 30%). Specifically, AFP-high tumours displayed significant activation of VEGF signalling (p?<?0.001), which might provide the rationale for the reported benefit of ramucirumab in this subgroup of patients

An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents

Program (HEPCAR, reference no. 667273-2); US Department of Defense(CA150272P3); an Accelerator Award (CRUCK, AECC, AIRC) (HUNTER,reference no. C9380/A26813), NCI Cancer Center Support Grant, National Cancer Institute; Tisch Cancer Institute (P30-CA196521); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute (SAF2016-76390); and the Generalitat de Catalunya/AGAUR (SGR-1358). Agrin Moeini is supported by Spanish National Health Institute. Sara Torrecilla and Judit Peix are funded by Centro de Investigación Biomedica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd-ISCIII). Carla Montironi is a recipient of Josep Font grant. Carmen Andreu-Oller is supported by "la Caixa" INPhINIT Fellowship Grant (LCF/BQ/IN17/11620024). Roser Pinyol is supported by HEPCAR and AECC. Daniela Sia is supported by the Gilead Sciences Research Scholar Program in Liver Disease. Scott L. Friedman is supported by the National Institutes of Health Research project grant (R01,DK5662) and US Department of Defense (CA150272P3). Mathias Heikenwälder was supported by an ERC Consolidator grant (HepatoMetaboPath), the SFBTR 209, 1335 and SFBTR179.Background & Aims: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. Methods: We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. Results: We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor β signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% confidence interval, 1.21-4.80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. Conclusions: We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis

Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is genetically characterized by the t(11;14)(q13;q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. Methodology/Principal Findings: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n=38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n=25) in the MCL cell lines and normal B lymphocytes confirmed that 80% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9,HOXA9,AHR,NR2F2 ,and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. Conclusions: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours

Advances in infrastructures and tools for multiagent systems

In the last few years, information system technologies have focused on solving challenges in order to develop distributed applications. Distributed systems can be viewed as collections of service-provider and ser vice-consumer components interlinked by dynamically defined workflows (Luck and McBurney 2008).Alberola Oltra, JM.; Botti Navarro, VJ.; Such Aparicio, JM. (2014). Advances in infrastructures and tools for multiagent systems. Information Systems Frontiers. 16:163-167. doi:10.1007/s10796-014-9493-6S16316716Alberola, J. M., Búrdalo, L., Julián, V., Terrasa, A., & García-Fornes, A. (2014). An adaptive framework for monitoring agent organizations. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9478-x .Alfonso, B., Botti, V., Garrido, A., & Giret, A. (2014). A MAS-based infrastructure for negotiation and its application to a water-right market. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9443-8 .Andrighetto, G., Castelfranchi, C., Mayor, E., McBreen, J., López-Sánchez, M., & Parsons, S. (2013). (Social) norm dynamics. In G. Andrighetto, G. Governatori, P. Noriega, & L. W. van der Torre (Eds.), Normative multi-agent systems (pp. 135–170). Dagstuhl: Schloss Dagstuhl--Leibniz-Zentrum fuer Informatik.Baarslag, T., Fujita, K., Gerding, E. H., Hindriks, K., Ito, T., Jennings, N. R., et al. (2013). Evaluating practical negotiating agents: results and analysis of the 2011 international competition. Artificial Intelligence, 198, 73–103.Boissier, O., Bordini, R. H., Hübner, J. F., Ricci, A., & Santi, A. (2013). Multi-agent oriented programming with JaCaMo. Science of Computer Programming, 78(6), 747–761.Campos, J., Esteva, M., López-Sánchez, M., Morales, J., & Salamó, M. (2011). Organisational adaptation of multi-agent systems in a peer-to-peer scenario. Computing, 91(2), 169–215.Carrera, A., Iglesias, C. A., & Garijo, M. (2014). Beast methodology: an agile testing methodology for multi-agent systems based on behaviour driven development. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9438-5 .Criado, N., Such, J. M., & Botti, V. (2014). Norm reasoning services. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9444-7 .Del Val, E., Rebollo, M., & Botti, V. (2014). Enhancing decentralized service discovery in open service-oriented multi-agent systems. Journal of Autonomous Agents and Multi-Agent Systems, 28(1), 1–30.Denti, E., Omicini, A., & Ricci, A. (2002). Coordination tools for MAS development and deployment. Applied Artificial Intelligence, 16(9–10), 721–752.Dignum, V., & Dignum, F. (2012). A logic of agent organizations. Logic Journal of IGPL, 20(1), 283–316.Ferber, J., & Gutknecht, O. (1998). A meta-model for the analysis and design of organizations in multi-agent systems. In Multi agent systems. Proceedings. International Conference on (pp. 128–135). IEEE.Fogués, R. L., Such, J. M., Espinosa, A., & Garcia-Fornes, A. (2014). BFF: a tool for eliciting tie strength and user communities in social networking services. Information Systems Frontiers, 16(2). doi: 10.1007/s10796-013-9453-6 .Garcia, E., Giret, A., & Botti, V. (2011). Evaluating software engineering techniques for developing complex systems with multiagent approaches. Information and Software Technology, 53(5), 494–506.Garcia-Fornes, A., Hübner, J., Omicini, A., Rodriguez-Aguilar, J., & Botti, V. (2011). Infrastructures and tools for multiagent systems for the new generation of distributed systems. Engineering Applications of Articial Intelligence, 24(7), 1095–1097.Jennings, N., Faratin, P., Lomuscio, A., Parsons, S., Sierra, C., & Wooldridge, M. (2001). Automated negotiation: prospects, methods and challenges. International Journal of Group Decision and Negotiation, 10(2), 199–215.Jung, Y., Kim, M., Masoumzadeh, A., & Joshi, J. B. (2012). 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Genomic complexity and IGHV mutational status are key predictors of outcome of chronic lymphocytic leukemia patients with TP53 disruption.

The clinical course of chronic lymphocytic leukemia (CLL) is extremely heterogeneous and while some patients achieve a normal lifespan, others succumb to the disease shortly after diagnosis. Recurrent chromosomal aberrations as detected by chromosome banding analysis (CBA) or fluorescent in situ hybridization (FISH) have a reproducible prognostic power in terms of response to therapy and survival.1–3 In particular, patients whose tumor cells harbor 17p deletions (17p-) are considered to have a shorter survival and, hence, high-risk CLL. This poor prognosis is, however, not universally true for all patients with 17p- CLL. Indeed, we and others have observed that some clinical-biological features, such as presence of B symptoms, advanced clinical stage, size of the 17p- clone, β2-microglobulin (β2M) concentration and IGH mutational status have a significant impact on the outcome of this subgroup of patients.4,5 Novel molecular studies have helped in the understanding of 17p- CLL. On one hand, TP53 mutations are present in more than 80% of cases with 17p deletion and in around 5% of patients without 17p deletion.6,7 On the other hand, next generation sequencing studies have revealed novel genetic aberrations such as NOTCH1 and SF3B1 mutations that have a negative impact on survival.8–10 Finally, genomic complexity, as defined by karyotyping1 or copy number (CN) arrays, has also been independently associated with disease transformation and poor outcome in patients with CLL.11,12 The aim of this study was to evaluate the prognostic value of concomitant molecular abnormalities in patients with CLL and TP53 aberrations as diagnosed by FISH, CBA or DNA sequencing

Regulation of N-WASP and the Arp2/3 Complex by Abp1 Controls Neuronal Morphology

Polymerization and organization of actin filaments into complex superstructures is indispensable for structure and function of neuronal networks. We here report that knock down of the F-actin-binding protein Abp1, which is important for endocytosis and synaptic organization, results in changes in axon development virtually identical to Arp2/3 complex inhibition, i.e., a selective increase of axon length. Our in vitro and in vivo experiments demonstrate that Abp1 interacts directly with N-WASP, an activator of the Arp2/3 complex, and releases the autoinhibition of N-WASP in cooperation with Cdc42 and thereby promotes N-WASP-triggered Arp2/3 complex-mediated actin polymerization. In line with our mechanistical studies and the colocalization of Abp1, N-WASP and Arp2/3 at sites of actin polymerization in neurons, we reveal an essential role of Abp1 and its cooperativity with Cdc42 in N-WASP-induced rearrangements of the neuronal cytoskeleton. We furthermore show that introduction of N-WASP mutants lacking the ability to bind Abp1 or Cdc42, Arp2/3 complex inhibition, Abp1 knock down, N-WASP knock down and Arp3 knock down, all cause identical neuromorphological phenotypes. Our data thus strongly suggest that these proteins and their complex formation are important for cytoskeletal processes underlying neuronal network formation

The nucleoporin ALADIN regulates Aurora A localization to ensure robust mitotic spindle formation

The formation of the mitotic spindle is a complex process that requires massive cellular reorganization. Regulation by mitotic kinases controls this entire process. One of these mitotic controllers is Aurora A kinase, which is itself highly regulated. In this study, we show that the nuclear pore protein ALADIN is a novel spatial regulator of Aurora A. Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment. ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition. Of interest, mutations in ALADIN cause triple A syndrome. We find that some of the mitotic phenotypes that we observe after ALADIN depletion also occur in cells from triple A syndrome patients, which raises the possibility that mitotic errors may underlie part of the etiology of this syndrome

SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism

Genetic mutations of SHANK3 have been reported in patients with intellectual disability, autism spectrum disorder (ASD) and schizophrenia. At the synapse, Shank3/ProSAP2 is a scaffolding protein that connects glutamate receptors to the actin cytoskeleton via a chain of intermediary elements. Although genetic studies have repeatedly confirmed the association of SHANK3 mutations with susceptibility to psychiatric disorders, very little is known about the neuronal consequences of these mutations. Here, we report the functional effects of two de novo mutations (STOP and Q321R) and two inherited variations (R12C and R300C) identified in patients with ASD. We show that Shank3 is located at the tip of actin filaments and enhances its polymerization. Shank3 also participates in growth cone motility in developing neurons. The truncating mutation (STOP) strongly affects the development and morphology of dendritic spines, reduces synaptic transmission in mature neurons and also inhibits the effect of Shank3 on growth cone motility. The de novo mutation in the ankyrin domain (Q321R) modifies the roles of Shank3 in spine induction and morphology, and actin accumulation in spines and affects growth cone motility. Finally, the two inherited mutations (R12C and R300C) have intermediate effects on spine density and synaptic transmission. Therefore, although inherited by healthy parents, the functional effects of these mutations strongly suggest that they could represent risk factors for ASD. Altogether, these data provide new insights into the synaptic alterations caused by SHANK3 mutations in humans and provide a robust cellular readout for the development of knowledge-based therapies