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[en] The fusion protein RUNX1-CBFA2T1 associated with t(8;21)-positive acute myeloid leukaemia is a potent inhibitor of haematopoetic differentiation. The role of RUNX1-CBFA2T1 in leukaemic cell proliferation is less clear. We examined the consequences of siRNA-mediated RUNX1-CBFA2T1 depletion regarding proliferation and clonogenicity of t(8;21)-positive cell lines. The t(8;21)-positive cell line Kasumi-1 was electroporated with RUNX1-CBFA2T1 or control siRNAs followed by analysis of proliferation, colony formation, cell cycle distribution, apoptosis and senescence. Electroporation of Kasumi-1 cells with RUNX1-CBFA2T1 siRNAs, but not with control siRNAs, resulted in RUNX1-CBFA2T1 suppression which lasted for at least 5 days. A single electroporation with RUNX1-CBFA2T1 siRNA severely diminished the clonogenicity of Kasumi-1 cells. Prolonged RUNX1-CBFA2T1 depletion inhibited proliferation in suspension culture and G1-S transition during the cell cycle, diminished the number of apoptotic cells, but induced cellular senescence. The addition of haematopoetic growth factors could not rescue RUNX1-CBFA2T1-depleted cells from senescence, and could only partially restore their clonogenicity. RUNX1-CBFA2T1 supports the proliferation and expansion of t(8;21)-positive leukaemic cells by preventing cellular senescence. These findings suggest a central role of RUNX1-CBFA2T1 in the maintenance of the leukaemia. Therefore, RUNX1-CBFA2T1 is a promising and leukaemia-specific target for molecularly defined therapeutic approaches
[en] Highlights: ► Inhibition of MAP4K3 by RNAi leads to increased mean lifespan in Caenorhabditis elegans. ► Mutation in the citron homology domain of MAP4K3 leads to increased mean lifespan. ► Mutation in the kinase domain of MAP4K3 has no significant effect on mean lifespan. -- Abstract: The TOR pathway is a kinase signaling pathway that regulates cellular growth and proliferation in response to nutrients and growth factors. TOR signaling is also important in lifespan regulation – when this pathway is inhibited, either naturally, by genetic mutation, or by pharmacological means, lifespan is extended. MAP4K3 is a Ser/Thr kinase that has recently been found to be involved in TOR activation. Unexpectedly, the effect of this protein is not mediated via Rheb, the more widely known TOR activation pathway. Given the role of TOR in growth and lifespan control, we looked at how inhibiting MAP4K3 in Caenorhabditiselegans affects lifespan. We used both feeding RNAi and genetic mutants to look at the effect of MAP4K3 deficiency. Our results show a small but significant increase in mean lifespan in MAP4K3 deficient worms. MAP4K3 thus represents a new target in the TOR pathway that can be targeted for pharmacological intervention to control lifespan.
[en] Endothelial dysfunction is a main feature of retinal neovascular diseases which are the leading cause of blindness in developed countries. Yes-associated protein (YAP) and signal transducer and activator of transcription factor 3 (STAT3) participate in angiogenesis via vascular endothelial growth factor (VEGF) signaling. Additionally, YAP can bind STAT3 in endothelial cells. In the study, dimethyloxalylglycine (DMOG) stimulated human retinal microvascular endothelial cells (HRMECs) was used as retinal endothelial hypoxia model. The proliferation of HRMECs, as well as t-YAP, p-STAT3 (Tyr705) increased, while p-YAP (Ser127), p-YAP (Ser397) decreased following hypoxia. Meanwhile, YAP and STAT3 translocated to the nucleus. YAP knockdown inhibited the proliferation, migration and tube formation of HRMECs. YAP overexpression up-regulated phosphorylation of STAT3. The YAP overexpression-induced HRMECs proliferation, migration and tube formation were reversed by S3I-201, a selective STAT3 inhibitor. YAP interacted with STAT3 to promote STAT3 nuclear translocation. Additionally, YAP and STAT3 promoted the transcription of VEGF synergistically. Finally, inhibition of YAP alleviated retinal pathological neovascularization in mouse oxygen-induced retinopathy (OIR) model. In summary, activated YAP interacted with STAT3 to promote the activation and nuclear translocation of STAT3, hence boosted the proliferation, migration and tube formation of HRMECs via VEGF signaling following hypoxia. The data will further elucidate the mechanisms of retinal neovascular diseases.
[en] Single pressure multi-fluid models have complex characteristics. This means that it is not properly posed for the initial value problem. Authors made the following conclusions for this issue: (1) Hyperbolicity of the corresponding system of partial differential equations is not a necessary condition for the development of a numerical model for multi-phase flow, but whether or not it is hyperbolic can provide guidance relative to initial conditions, boundary conditions, and expected high frequency behavior of the model. (2) A necessary condition for a well-posed numerical model is stability in the von Neumann sense, i.e. growth factor less than 1.0 for the shortest wave-length, 2Δx. (3) The smallest node size used for convergence studies should be of the order of the characteristic dimension of the average description. In this paper, the semi-implicit solution scheme of SPACE is studied whether it is in accordance with these conclusions
[en] This paper investigates the average trapping time (ATT) on weighted scale-free m-triangulation networks. ATT is the mean of the first-passage time from any node to the trap fixed at a hub node over the entire network. Based on the structural properties of weighted scale-free m-triangulation networks, we deduce the accurate expression of ATT for weight-dependent walk. The result shows that the scaling expression of ATT with network size obeys a power-law function with exponent characterized by the weight factor r and the growth factor m. Further, we find that the parameters r and m have a significant impact on the diffusion efficiency of the network, namely, the smaller r and m are, the more efficient the trapping process of the network is. (paper: classical statistical mechanics, equilibrium and non-equilibrium)
[en] Due to their high ionic conductivity, solid polymer electrolyte (SPE) systems have attracted wide spread attention as the most appropriate choice to fabricate all-solid-state electrochemical devices, namely batteries, sensors and fuel cells. In this work, ion conductive polymer electrolyte membranes have been prepared for battery fabrication. However, fractals were found to grow in these polymer electrolyte membranes weeks after they were prepared. It was believed that the formation of fractal aggregates in these membranes were due to ionic movement. The discovery of fractal growth pattern can be used to understand the effects of such phenomenon in the polymer electrolyte membranes. Digital images of the fractal growth patterns were taken and a simulation model was developed based on the Brownian motion theory and a fractal dialect known as L-system. A computer coding has been designed to simulate and visualize the fractal growth. (author)
[en] Highlights: • Chemical coupling of the antimicrobial peptide LL37 was tested. • Coupling of LL37 to sensor electrodes enabled immediate functional read-outs. • PEG spacer mediated immobilization of LL37 induced endothelial cell proliferation. • Mitogenic effects of LL37 were mimicking responses to soluble VEGF. The chemical coupling of growth factors to solid substrates are discussed as an alternative to delivery systems. Utilizing entire proteins for this application is hampered by safety and stability considerations. Instead, growth factor mimicking peptides are of great interest for biomedical applications, such as tissue engineering, due to their purity and stability. The human cathelicidin derived antimicrobial peptide LL37, beside its microbicidal activity, was shown to stimulate endothelial cell growth when used in a soluble form. Here, in a novel approach, spacer mediated immobilization, but not direct conjugation of LL37, to a gold substrate was shown to result in a pronounced mitogenic effect on endothelial cells, comparable to that of soluble vascular endothelial growth factor.
[en] We study the effect of noise on the evolution of the growth factor of density perturbations in the context of the ΛCDM model. Stochasticity is introduced as a Wiener process amplified by an intensity parameter α. By comparing the evolution of deterministic and stochastic cases for different values of α we estimate the intensity level necessary to make noise relevant for cosmological tests based on large-scale structure data. Our results indicate that the presence of random forces underlying the fluid description can lead to significant deviations from the nonstochastic solution at late times for α≥10-3.
[en] CTCF, a nuclear transcriptional factor, is a multifunctional protein and involves regulation of growth factor- and cytokine-induced cell proliferation/differentiation. In the present study, we investigated the role of CTCF in protecting stress-induced apoptosis in various human cell types. We found that UV irradiation and hyper-osmotic stress induced human corneal epithelial (HCE) and hematopoietic myeloid cell apoptosis detected by significantly increased caspase 3 activity and decreased cell viability. The stress-induced apoptotic response in these cells requires down-regulation of CTCF at both mRNA and protein levels, suggesting that CTCF may play an important role in downstream events of stress-induced signaling pathways. Inhibition of NFκB activity prevented stress-induced down-regulation of CTCF and increased cell viability against stress-induced apoptosis. The anti-apoptotic effect of CTCF was further studied by manipulating CTCF activities in HCE and hematopoietic cells. Transient transfection of cDNAs encoding full-length human CTCF markedly suppressed stress-induced apoptosis in these cells. In contrast, knocking down of CTCF mRNA using siRNA specific to CTCF significantly promoted stress-induced apoptosis. Thus, our results reveal that CTCF is a down stream target of stress-induced signaling cascades and it plays a significant anti-apoptotic role in regulation of stress-induced cellular responses in HCE and hematopoietic myeloid cells
[en] This study was performed to characterize the interaction of epidermal growth factor and radiation in two human head and neck squamous cell cancer cell lines of vastly different radiosensitivities (UM-SCC-6 radiosensitive; UM-SCC-1 radioresistant). It was determined that exposure to epidermal growth factor (10 ng/ml) for 24 h prior to radiation resulted in radiosensitization in both cell lines, however, the magnitude of radiosensitization was greater in the radiosensitive UM-SCC-6 cells compared to the radioresistant UM-SCC-1 cells. Treatment of the UM-SCC-6 cells with epidermal growth factor (EGF) (10 ng/ml) for 24 h resulted in a growth delay, however, cell growth returned to normal approximately 26 h following removal of EGF. Similar treatment of the UM-SCC-1 cells resulted in no growth inhibition. The 24 h preradiation exposures to EGF (10 ng/ml) did not affect the radiation-induced growth delay in either cell line. Additionally, the 24 h exposures to EGF (10 ng/ml) did not cause the cells to enter a more radiosensitive cell cycle phase. Further work will be necessary to determine whether events associated with the EGF-induced growth delay in the UM-SCC-6 cells are associated with the enhanced EGF-induced radiosensitization in these cells compared to UM-SCC-1 cells. 11 refs., 2 figs., 2 tabs