Although ganglioside GD3 levels are highly elevated in malignant melanomas, the role of GD3 in melanomas' malignant properties has not been clearly shown. To investigate this problem, we genetically generated GD3-positive (GD3 ؉ ) transfectant cells from a GD3-negative (GD3 ؊ ) mutant line SK-MEL-28-N1 and analyzed the phenotypic changes in the transfected cells. GD3 ؉ cells showed markedly increased cell growth and invasive characteristics. Two bands that underwent stronger tyrosine phosphorylation in GD3 ؉ cell lines than in controls after treatment with FCS were found with molecular masses of 130 and 68 kDa. They were identified as p130Cas and paxillin by sequential immunoprecipitation. Their roles in cell growth and invasion were analyzed with a small interfering RNA (siRNA) approach. Cell growth, as analyzed by BrdUrd uptake, was strongly suppressed in GD3 ؉ cells to near the levels of GD3 ؊ cells when treated with siRNA for p130Cas but not when treated with siRNA for paxillin. However, treatment with siRNAs of either p130Cas or paxillin resulted in the marked suppression of the invasive activity of GD3 ؉ cells almost to the levels of control cells. These results suggested that these two molecules function as effectors of GD3-mediated signaling, leading to such malignant properties as rapid cell growth and invasion.small interfering RNA ͉ sialyltransferase ͉ phosphorylation

Multi-Issue Negotiation protocols have been studied very widely and represent a promising field since most of negotiation problems in the realworld are complex ones including multiple issues. In particular, in reality issues are constrained each other. This makes agents' utilities nonlinear. There have been a lot of work on multi-issue negotiations. However, there have been very few work that focus on nonlinear utility spaces. In this paper, we assume agents have nonlinear utility spaces. For the linear utility domain, agents can aggregate the utilities of the issue-values by simple linear summation. In the real world, such aggregations are unrealistic. For example, we cannot just add up the value of car's tires and the value of car's engine when engineers design a car. In this paper, we propose an auction-based multiple-issue negotiation protocol among nonlinear util-1 ity agents. Our negotiation protocol employs several techniques, i.e., adjusting sampling, auction-based maximization of social welfare. Our experimental results show that our method can outperform the existing simple methods in particular in the huge utility space that can be often found in the real-world. Further, theoretically, our negotiation protocol can guarantee the completeness if some conditions are satisfied.

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BackgroundHuman-assisted reproductive technologies (ART) are a widely accepted treatment for infertile couples. At the same time, many studies have suggested the correlation between ART and increased incidences of normally rare imprinting disorders such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). Major methylation dynamics take place during cell development and the preimplantation stages of embryonic development. ART may prevent the proper erasure, establishment, and maintenance of DNA methylation. However, the causes and ART risk factors for these disorders are not well understood.ResultsA nationwide epidemiological study in Japan in 2015 in which 2777 pediatrics departments were contacted and a total of 931 patients with imprinting disorders including 117 BWS, 227 AS, 520 PWS, and 67 SRS patients, were recruited. We found 4.46- and 8.91-fold increased frequencies of BWS and SRS associated with ART, respectively. Most of these patients were conceived via in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and showed aberrant imprinted DNA methylation. We also found that ART-conceived SRS (ART-SRS) patients had incomplete and more widespread DNA methylation variations than spontaneously conceived SRS patients, especially in sperm-specific methylated regions using reduced representation bisulfite sequencing to compare DNA methylomes. In addition, we found that the ART patients with one of three imprinting disorders, PWS, AS, and SRS, displayed additional minor phenotypes and lack of the phenotypes. The frequency of ART-conceived Prader-Willi syndrome (ART-PWS) was 3.44-fold higher than anticipated. When maternal age was 37 years or less, the rate of DNA methylation errors in ART-PWS patients was significantly increased compared with spontaneously conceived PWS patients.ConclusionsWe reconfirmed the association between ART and imprinting disorders. In addition, we found unique methylation patterns in ART-SRS patients, therefore, concluded that the imprinting disorders related to ART might tend to take place just after fertilization at a time when the epigenome is most vulnerable and might be affected by the techniques of manipulation used for IVF or ICSI and the culture medium of the fertilized egg.Electronic supplementary materialThe online version of this article (10.1186/s13148-019-0623-3) contains supplementary material, which is available to authorized users.

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