A Meta-Heuristic Optimization Procedure for the Identification of the Nonlinear Model Parameters of Hydraulic Dampers Based on Experimental Dataset of Real Working Conditions

Hydralic dampers are widely implemented in railway vehicle suspension stages, especially in high-speed passenger trains. They are designed to be mounted in different positions to improve comfort, stability, and safety performances. Numerical simulations are often used to assist the design and optimization of these components. Unfortunately, hydraulic dampers are highly nonlinear due to the complex fluid dynamic phenomena taking place inside the chambers and through the by-pass orifices. This requires accurate damper models to be developed to estimate the influence of the nonlinearities of such components during the dynamic performances of the whole vehicle. This work aims at presenting a new parametric damper model based on a nonlinear lumped element approach. Moreover, a new model tuning procedure will be introduced. Differently from the typical sinusoidal characterization cycles, this routine is based on experimental tests of real working conditions. The set of optimal model parameters will be found through a metaheuristic iterative approach able to minimize the differences between numerical and experimental damper forces. The performances of the optimal model will be compared with the ones of the most common Maxwell model generally implemented in railway multibody software programs

A single-cell analysis of breast cancer cell lines to study tumour heterogeneity and drug response

Cancer cells within a tumour have heterogeneous phenotypes and exhibit dynamic plasticity. How to evaluate such heterogeneity and its impact on outcome and drug response is still unclear. Here, we transcriptionally profile 35,276 individual cells from 32 breast cancer cell lines to yield a single cell atlas. We find high degree of heterogeneity in the expression of biomarkers. We then train a deconvolution algorithm on the atlas to determine cell line composition from bulk gene expression profiles of tumour biopsies, thus enabling cell line-based patient stratification. Finally, we link results from large-scale in vitro drug screening in cell lines to the single cell data to computationally predict drug responses starting from single-cell profiles. We find that transcriptional heterogeneity enables cells with differential drug sensitivity to co-exist in the same population. Our work provides a framework to determine tumour heterogeneity in terms of cell line composition and drug response

Hematopoietic stem cell transplantation is effective curative treatment in pediatric refractory/aggressive Langerhans cell histiocytosis

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Iron up-modulates the expression of transferrin receptors during monocyte-macrophage maturation

Abstract We have investigated the effect of iron on the expression of transferrin receptors (TrfRs) and ferritin chains in cultures of human peripheral blood monocytes maturing to macrophages. Monocyte-macrophage maturation is associated with a gradual rise of Trf-binding capacity in the absence of cell proliferation. At all culture times, treatment with ferric ammonium citrate induces a dose-dependent rise of the Trf-binding level as compared with nontreated cells. Scatchard analysis revealed that this phenomenon is due to an increase in receptor number rather than an alteration in ligand-receptor affinity. Biosynthesis experiments indicated that the rise in number of TrfRs is due to an increase of receptor synthesis, which is associated with a sustained elevation of the TrfR RNA level. The up-regulation of TrfR synthesis is specific in that expression of other macrophage membrane proteins is not affected by iron addition. Conversely, addition of an iron chelator induced a slight decrease of TrfR synthesis. The expression of heavy and light ferritin chains at RNA and protein levels was markedly more elevated in cultured macrophages than in fresh monocytes, thus suggesting modulation of ferritin genes at transcriptional or post-transcriptional levels. Addition of iron salts to monocyte-macrophage cultures sharply stimulated ferritin synthesis but only slightly enhanced the level of ferritin RNA, thus indicating a modulation at the translational level. These results suggests that in cultured human monocytes-macrophages, iron up-regulates TrfR expression, thus in sharp contrast to the negative feedback reported in a variety of other cell types. These observations may shed light on the mechanism(s) of iron storage in tissue macrophages under normal conditions and possibly on the pathogenesis of diseases characterized by abnormal iron storage

Identification and characterization of a novel SCYL3-NTRK1 rearrangement in a colorectal cancer patient

In colorectal cancer patients, chromosomal rearrangements involving NTRK1 gene (encoding the TRKA protein) are shown in a small subset of patients and are associated with the constitutive activation of the kinase domain of TRKA. In turn, activated TRKA-fusion proteins are associated with proliferation and survival in colorectal cancer tumors. Here we report the identification and functional characterization of a new SCYL3-NTRK1 fusion gene in a 61-year-old colorectal cancer patient. To our knowledge, this fusion protein has never been previously documented in oncological patients. We show that this novel fusion is oncogenic and sensitive to TRKA inhibitors. As suggested by other pieces of evidence, entrectinib - an orally available pan- TRK, ROS1 and ALK inhibitor - may have particular efficacy in patients with NTRK rearrangements. Therefore, screening for rearrangements involving NTRK genes may help identifying a subset of patients able to derive benefit from treatment with entrectinib or other targeted inhibitors

Cross platform microarray analysis for robust identification of differentially expressed genes

<p>Abstract</p> <p>Background</p> <p>Microarrays have been widely used for the analysis of gene expression and several commercial platforms are available. The combined use of multiple platforms can overcome the inherent biases of each approach, and may represent an alternative that is complementary to RT-PCR for identification of the more robust changes in gene expression profiles.</p> <p>In this paper, we combined statistical and functional analysis for the cross platform validation of two oligonucleotide-based technologies, Affymetrix (AFFX) and Applied Biosystems (ABI), and for the identification of differentially expressed genes.</p> <p>Results</p> <p>In this study, we analysed differentially expressed genes after treatment of an ovarian carcinoma cell line with a cell cycle inhibitor. Treated versus control RNA was analysed for expression of 16425 genes represented on both platforms.</p> <p>We assessed reproducibility between replicates for each platform using CAT plots, and we found it high for both, with better scores for AFFX. We then applied integrative correlation analysis to assess reproducibility of gene expression patterns across studies, bypassing the need for normalizing expression measurements across platforms. We identified 930 genes as differentially expressed on AFFX and 908 on ABI, with ~80% common to both platforms. Despite the different absolute values, the range of intensities of the differentially expressed genes detected by each platform was similar. ABI showed a slightly higher dynamic range in FC values, which might be associated with its detection system. 62/66 genes identified as differentially expressed by Microarray were confirmed by RT-PCR.</p> <p>Conclusion</p> <p>In this study we present a cross-platform validation of two oligonucleotide-based technologies, AFFX and ABI. We found good reproducibility between replicates, and showed that both platforms can be used to select differentially expressed genes with substantial agreement. Pathway analysis of the affected functions identified themes well in agreement with those expected for a cell cycle inhibitor, suggesting that this procedure is appropriate to facilitate the identification of biologically relevant signatures associated with compound treatment. The high rate of confirmation found for both common and platform-specific genes suggests that the combination of platforms may overcome biases related to probe design and technical features, thereby accelerating the identification of trustworthy differentially expressed genes.</p

Innovative passive yaw damper to increase the stability and curve-taking performance of high-speed railway vehicles

Yaw dampers are implemented on high-speed trains to reduce their tendency towards unstable movement (hunting) while running at high-speed. Although they have a positive influence on the vehicle's stability, these devices impose a steering resistance action on the bogies while negotiating tight curves at low speed, and so standard passive devices must be designed taking conflicting objective functions into account. This paper presents an innovative yaw damper able to overcome this trade-off by introducing a passive solution able to modify this component's working behaviour during different vehicle operating conditions. To quantify the efficacy of this solution, numerical models of innovative and standard dampers were developed and validated by means of experimental tests. Then, they were co-simulated with a multibody model of a real test case vehicle running under different operating conditions