Background Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression. Methods Bioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth. Results FOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo. Conclusion The FOXM1–KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1202-3) contains supplementary material, which is available to authorized users.

It is of both fundamental and practical interest to study the flow physics in the manipulation of droplets. In this paper, we investigate complex flow in liquid droplets actuated by a linear gradient of wettability using dissipative particle dynamics simulation. The wetting property of the substrate ranging from hydrophilic to hydrophobic is achieved by adjusting the conservative solid-liquid interactions which results in a variation of solid-liquid surface tension. The internal three-dimensional velocity field with transverse flow in droplet is revealed and analyzed in detail. When the substrate is hydrophobic, it is found that there is slight deformation but strong flow circulation inside the droplet, and the droplet rolling is the dominant mechanism for the movement. However, large deformation of the droplet is generated after the droplet reaches the hydrophilic surface, and a mechanism combining rolling and sliding dominates the transportation of the droplet. Another interesting finding is that the thermal fluctuation can accelerate the spontaneous motion of a liquid droplet under a wetting gradient. The effects of the steepness of wetting gradient and the size of droplet on the translation speed are studied as well.

Cancer develops and progresses often by inactivating p53. Here, we unveil nerve growth factor receptor (NGFR, p75NTR or CD271) as a novel p53 inactivator. p53 activates NGFR transcription, whereas NGFR inactivates p53 by promoting its MDM2-mediated ubiquitin-dependent proteolysis and by directly binding to its central DNA binding domain and preventing its DNA-binding activity. Inversely, NGFR ablation activates p53, consequently inducing apoptosis, attenuating survival, and reducing clonogenic capability of cancer cells, as well as sensitizing human cancer cells to chemotherapeutic agents that induce p53 and suppressing mouse xenograft tumor growth. NGFR is highly expressed in human glioblastomas, and its gene is often amplified in breast cancers with wild type p53. Altogether, our results demonstrate that cancers hijack NGFR as an oncogenic inhibitor of p53.DOI: http://dx.doi.org/10.7554/eLife.15099.001

Molecular dynamics simulation is utilized to investigate the ionic transport of NaCl in solution through a graphene nanopore under an applied electric field. Results show the formation of concentration polarization layers in the vicinity of the graphene sheet. The nonuniformity of the ion distribution gives rise to an electric pressure which drives vortical motions in the fluid if the electric field is sufficiently strong to overcome the influence of viscosity and thermal fluctuations. The relative importance of hydrodynamic transport and thermal fluctuations in determining the pore conductivity is investigated. A second important effect that is observed is the mass transport of water through the nanopore, with an average velocity proportional to the applied voltage and independent of the pore diameter. The flux arises as a consequence of the asymmetry in the ion distribution which can be attributed to differing mobilities of the sodium and chlorine ions, and, to the polarity of water molecules. The accumulation of liquid molecules in the vicinity of the nanopore due to reorientation of the water dipoles by the local electric field is seen to result in a local increase in the liquid density. Results confirm that the electric conductance is proportional to the nanopore diameter for the parameter regimes that we simulated. The occurrence of fluid vortices is found to result in an increase in the effective electrical conductance.

Continuum simulation is employed to study ion transport and fluid flow through a nanopore in a solid-state membrane under an applied potential drop. Results show the existence of concentration polarization layers on the surfaces of the membrane. The nonuniformity of the ionic distribution gives rise to an electric pressure that drives vortical motion in the fluid. There is also a net hydrodynamic flow through the nanopore due to an asymmetry induced by the membrane surface charge. The qualitative behavior is similar to that observed in a previous study using molecular dynamic simulations. The current–voltage characteristics show some nonlinear features but are not greatly affected by the hydrodynamic flow in the parameter regime studied. In the limit of thin Debye layers, the electric resistance of the system can be characterized using an equivalent circuit with lumped parameters. Generation of vorticity can be understood qualitatively from elementary considerations of the Maxwell stresses. However, the flow strength is a strongly nonlinear function of the applied field. Combination of electrophoretic and hydrodynamic effects can lead to ion selectivity in terms of valences and this could have some practical applications in separations.

BackgroundRecent evidence suggests that the aberrant activation of Hedgehog (Hh) signaling by Gli transcription factors is characteristic of a variety of aggressive human carcinomas, including colorectal cancer (CRC). Forkhead box M1 (FoxM1) controls the expression of a number of cell cycle regulatory proteins, and FoxM1 expression is elevated in a broad range of human malignancies, which suggests that it plays a crucial role in tumorigenesis. However, the mechanisms underlying FoxM1 expression are not fully understood. Here, we aim to further investigate the molecular mechanism by which Gli1 regulates FoxM1 in CRC.MethodsWestern blotting and immunohistochemistry (IHC) were used to evaluate FoxM1 and Gli1 protein expression, respectively, in CRC tissues and matched adjacent normal mucosa. BrdU (5-bromo-2′-deoxyuridine) and clone formation assays were used to clarify the influence of FoxM1 on CRC cell growth and proliferation. Chromatin immunoprecipitation (ChIP) and luciferase experiments were performed to explore the potential mechanisms by which Gli1 regulates FoxM1. Additionally, the protein and mRNA expression levels of Gli1 and FoxM1 in six CRC cell lines were measured using Western blotting and real-time PCR. Finally, the effect of Hh signaling on the expression of FoxM1 was studied in cell biology experiments, and the effects of Hh signaling activation and FoxM1 inhibition on the distribution of CRC cells among cell cycle phases was assessed by flow cytometry.ResultsGli1 and FoxM1 were abnormally elevated in human CRC tissues compared with matched adjacent normal mucosa samples, and FoxM1 is a downstream target gene of the transcription factor Gli1 in CRC and promoted CRC cell growth and proliferation. Moreover, the aberrant activation of Hh signaling promoted CRC cell proliferation by directly binding to the promoter of FoxM1 and transactivating the activity of FoxM1 in CRC cells.ConclusionThe dysregulation of the Hh-Gli1-FoxM1 axis is essential for the proliferation and growth of human CRC cells and offers a potent target for therapeutic intervention in CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0491-7) contains supplementary material, which is available to authorized users.

Phanerozoic large igneous provinces (LIPs) have a significant influence on global climate changes and mass extinction events (MEEs). Most of the Global Boundary Stratotype Section and Points in the Phanerozoic international chronostratigraphic scale are coeval with LIPs and are marked in the sedimentary record by global-scale MEEs and/or by ocean anoxic events represented by black shales. However, due to limited knowledge on atmospheric oxygen concentrations, ocean redox conditions, and early fossils during the Meso-Neoproterozoic Eras prior to the Ediacaran period, little is known on the climate and environmental effects of LIPs during this period of a billion years, the so-called "Boring Billion" (1.8-0.8 Ga). Here we provide geochronological and geological evidence for a temporal and genetic link between the intense ca. 1380 Ma LIP activity (found on many crustal blocks) and coeval black shales in the Nuna (Columbia) supercontinent. We further propose that the ca. 1380 Ma LIPs and black shales widely distributed in the Nuna supercontinent represent a global-scale geological event and provide a robust natural marker for the Calymmian-Ectasian boundary at 1383 Ma. Further investigation of the temporal and genetic link between the LIPs and black shales at other times can contribute to understanding the variations in atmospheric oxygen concentrations and ocean redox conditions during the Boring Billion, during which virtually nothing of Earth's climate and MEEs is known.

A low-dimensional Galerkin method, initiated by Noack and Eckelmann ͓Physica D 56, 151 ͑1992͔͒, for the prediction of the flow field around a stationary two-dimensional circular cylinder in a uniform stream at low Reynolds number is generalized to the case of a rotating and translating cylinder. The Hopf bifurcation describing the transition from steady to time-periodic solution is investigated. A curve indicating the transitional boundary is given in the two-dimensional parameter plane of Reynolds number Re and rotating parameter ␣. Our results show that rotation may delay the onset of vortex street and decrease the vortex-shedding frequency. © 1996 American Institute of Physics. ͓S1070-6631͑96͒00107-9͔The problem of the flow around a uniformly rotating and translating circular cylinder has been investigated by several researchers due to its engineering importance and academic interest. Badr et al. 1 numerically simulated the steady and unsteady flow past a rotating circular cylinder at low Reynolds numbers Re with rotating parameter ␣, in which Re is based on the cylinder radius R and the incoming velocity U ϱ and ␣ϭR /U ϱ , where represents the angular velocity of the rotating cylinder. Ingham, 2 Ingham and Tang, 3 D'Alessio and Dennis 4 considered numerical solutions of the steadystate N-S equation at subcritical Re. The investigations of the unsteady flow for supercritical Reynolds numbers are relatively fewer than the case of the steady-state flow. Badr et al. 5 numerically studied the time-dependent flow past an impulsively rotating and translating circular cylinder started from rest for ReϾ200, while Coutanceau and Menard 6 gave corresponding experimental results. Chang and Chen 7 investigated the same problem at some higher Re for 0р␣Ͻ2, and suggested there are three modes of vortex shedding existing in wakes depending on Re and ␣.Meanwhile, the research on the bifurcation structure in an open-flow at low Reynolds numbers is of great interest. Provansal et al., 8 Sreenivasan et al., 9 and Schumm et al. 10 experimentally studied the onset of 2-D vortex shedding in the wakes behind a stationary circular cylinder and showed that the transition from the steady to the periodic flow is characterized by a Hopf bifurcation and can be described by the Stuart-Landau equation. Jackson, 11 Zebib 12 and Noack et al. 13,14 numerically investigated the onset of vortex shedding in flow past a stationary circular cylinder by applying the linear stability analysis to an autonomous dynamical system.Following Noack's work, 13 a low-dimensional Galerkin method ͑LDGM͒ is generalized to the case of a 2-D uniformly rotating and translating circular cylinder. Although the LDGM cannot compete with grid-based computational techniques for high accurate simulations of the velocity fields or the resolution of far-wake properties, it is confirmed to be an ideal tool for investigations on global stability and chaos-theoretical analysis. 13,14 In the present Galerkin method, the streamfunction is approximated by a finite ex- BRIEF CO...