It has been hypothesized that topological structures of biological transport networks are consequences of energy optimization. Motivated by experimental observation, we propose that adaptation dynamics may underlie this optimization. In contrast to the global nature of optimization, our adaptation dynamics responds only to local information and can naturally incorporate fluctuations in flow distributions. The adaptation dynamics minimizes the global energy consumption to produce optimal networks, which may possess hierarchical loop structures in the presence of strong fluctuations in flow distribution. We further show that there may exist a new phase transition as there is a critical open probability of sinks, above which there are only trees for network structures whereas below which loops begin to emerge.
This in vivo time-lapse imaging study in zebrafish reveals how changes to brain blood flow drive vessel pruning via endothelial cell migration, and how pruning leads to the simplification of the brain vasculature during development.
Many antimicrobial peptides (AMPs) selectively target and form pores in microbial membranes. However, the mechanisms of membrane targeting, pore formation and function remain elusive. Here we report an experimentally guided unbiased simulation methodology that yields the mechanism of spontaneous pore assembly for the AMP maculatin at atomic resolution. Rather than a single pore, maculatin forms an ensemble of structurally diverse temporarily functional low-oligomeric pores, which mimic integral membrane protein channels in structure. These pores continuously form and dissociate in the membrane. Membrane permeabilization is dominated by hexa-, hepta- and octamers, which conduct water, ions and small dyes. Pores form by consecutive addition of individual helices to a transmembrane helix or helix bundle, in contrast to current poration models. The diversity of the pore architectures—formed by a single sequence—may be a key feature in preventing bacterial resistance and could explain why sequence–function relationships in AMPs remain elusive.
Continuum models are derived for the moving contact line problem through a combination of macroscopic and microscopic considerations. Macroscopic thermodynamic argument is used to place constraints on the form of the boundary conditions at the solid surface and the contact line. This information is then used to set up molecular dynamics to measure the detailed functional dependence of the boundary conditions. Long range molecular forces are taken into account in the form of a surface potential. This allows us to handle the case of complete wetting as well as the case of partial wetting. In particular, we obtain a new continuum model for both cases in a unified form. Two main parameters and different spreading regimes are identified from the analysis of the energy dissipations for the continuum model. Scaling laws in these different regimes are derived. The new continuum model also allows us to derive boundary conditions for the lubrication approximation. Numerical results are presented for the thin film model, and the effect of the boundary condition is investigated.
BackgroundMetformin, which is widely used as an antidiabetic agent, has recently been reported to reduce cancer risk and improve prognosis in certain malignancies. However, the specific mechanisms underlying the effect of metformin on the development and progression of several cancers including oral squamous cell carcinoma (OSCC) remain unclear. In the present study, we investigated the effects of metformin on OSCC cells in vitro and in vivo.MethodsOSCC cells treated with or without metformin were counted using a hemocytometer. The clonogenic ability of OSCC cells after metformin treatment was determined by colony formation assay. Cell cycle progression and apoptosis were assessed by flow cytometry, and the activation of related signaling pathways was examined by immunoblotting. The in vivo anti-tumor effect of metformin was examined using a xenograft mouse model. Immunohistochemistry and TUNEL staining were used to determine the expression of cyclin D1 and the presence of apoptotic cells in tumors from mice treated with or without metformin.ResultsMetformin inhibited proliferation in the OSCC cell lines CAL27, WSU-HN6 and SCC25 in a time- and dose-dependent manner, and significantly reduced the colony formation of OSCC cells in vitro. Metformin induced an apparent cell cycle arrest at the G0/G1 phase, which was accompanied by an obvious activation of the AMP kinase pathway and a strongly decreased activation of mammalian target of rapamycin and S6 kinase. Metformin treatment led to a remarkable decrease of cyclin D1, cyclin-dependent kinase (CDK) 4 and CDK6 protein levels and phosphorylation of retinoblastoma protein, but did not affect p21 or p27 protein expression in OSCC cells. In addition, metformin induced apoptosis in OSCC cells, significantly down-regulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulating the pro-apoptotic protein Bax. Metformin also markedly reduced the expression of cyclin D1 and increased the numbers of apoptotic cells in vivo, thus inhibiting the growth of OSCC xenografts.ConclusionsOur data suggested that metformin could be a potential candidate for the development of new treatment strategies for human OSCC.
We derive a set of equations for the dynamics of evolving fluid membranes, such as cell membranes, in the presence of bulk fluids. We model the membrane as a surface endowed with a director field, which describes the local average orientation of the molecules on the membrane. A model for the elastic energy of a surface endowed with a director field is derived using liquid crystal theory. This elastic energy reduces to the well-known Helfrich energy in the limit when the directors are constrained to be normal to the surface. We then derive the full dynamic equations for the membrane that incorporate both the elastic and viscous effects, with and without the presence of bulk fluids. We also consider the effect of local spontaneous curvature, arising from the presence of membrane proteins. Overall, the systems of equations allow us to carry out stable, accurate, and robust numerical modeling for the dynamics of the membranes.
The mechanism of transmembrane ion permeation is studied using charged methyl guanidine as a model ion. With a widely applied reaction coordinate, our umbrella sampling results reveal a significant finite-size effect in small simulation systems and a serious hysteresis in large systems. Therefore, it is important to re-examine the simulation techniques for studying transmembrane permeation mechanism of ions suggested in previous works. In this work, two novel collective variables are designed to acquire a continuous trajectory of the permeation process and small statistical errors through umbrella sampling. A water-bridge mechanism is discussed in detail. In this mechanism, a continuous water chain (or a chain of water molecules and lipid head groups) is formed across the membrane to conduct the transmembrane permeation of charged methyl guanidine. We obtain a continuous transition trajectory by combining the two-dimensional umbrella sampling in the local region of the saddle state and a one-dimensional sampling in the out region. Our free energy analysis shows that, with the presence of the water bridge, the energy barrier of the transmembrane permeation of ions is reduced significantly. Our analysis suggests that the water-bridge mechanism is common for permeation of ions across thick membranes, including palmitoyloleoyl phosphocholine and dipalmitoylphosphatidylcholine membranes.
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