13 research outputs found
Computational Analyses of Synergism in Small Molecular Network Motifs
<div><p>Cellular functions and responses to stimuli are controlled by complex regulatory networks that comprise a large diversity of molecular components and their interactions. However, achieving an intuitive understanding of the dynamical properties and responses to stimuli of these networks is hampered by their large scale and complexity. To address this issue, analyses of regulatory networks often focus on reduced models that depict distinct, reoccurring connectivity patterns referred to as motifs. Previous modeling studies have begun to characterize the dynamics of small motifs, and to describe ways in which variations in parameters affect their responses to stimuli. The present study investigates how variations in pairs of parameters affect responses in a series of ten common network motifs, identifying concurrent variations that act synergistically (or antagonistically) to alter the responses of the motifs to stimuli. Synergism (or antagonism) was quantified using degrees of nonlinear blending and additive synergism. Simulations identified concurrent variations that maximized synergism, and examined the ways in which it was affected by stimulus protocols and the architecture of a motif. Only a subset of architectures exhibited synergism following paired changes in parameters. The approach was then applied to a model describing interlocked feedback loops governing the synthesis of the CREB1 and CREB2 transcription factors. The effects of motifs on synergism for this biologically realistic model were consistent with those for the abstract models of single motifs. These results have implications for the rational design of combination drug therapies with the potential for synergistic interactions.</p></div
The model of Song et al. [26] and simulations.
<p>(<b>A1</b>) The feedback loops described by the model. (<b>A2</b>) After 5 pulses of 5-HT treatment, CREB1 and CREB2 switch from a LOW state to a HIGH state. (<b>B</b>) The NB curve and AE curve for the parameter pair <i>V<sub>x</sub></i>/<i>k<sub>dy</sub></i>. This pair shows strong NB synergism, and additive synergism.</p
For Variant M (<i>S</i> = 1), the histograms of synergism degrees from 91 parameter pairs were compared between standard parameter values and varied parameter values.
<p>(<b>A</b>) The stimulus and response curves of A (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003524#pcbi.1003524.e001" target="_blank">Eq. 1</a>) and B (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003524#pcbi.1003524.e002" target="_blank">Eq. 2</a>) with standard parameter values (<b>A1</b>) and with parameters altered to give slower B dynamics (orange trace), or delayed B dynamics (green trace), with dynamics of A unchanged (black trace) (<b>A2</b>). (<b>B</b>) The histograms of NB synergism (<b>B1</b>) and additive synergism (<b>B2</b>) degrees with standard parameter values (grey bars) and with parameters altered to give slower B dynamics (orange bars) or delayed B dynamics (green bars). (<b>C</b>) The histograms of NB synergism (<b>C1</b>) and additive synergism (<b>C2</b>) degrees with standard parameter values (grey bars), with <i>k<sub>ST</sub></i> increased by 25% (red bars), and with <i>k<sub>ST</sub></i> reduced by 25% (pink bars). (<b>D</b>) The histograms of NB synergism (<b>D1</b>) and additive synergism (<b>D2</b>) degrees with standard values (grey bars), <i>K<sub>T</sub></i> increased by 25% (dark brown bars), and <i>K<sub>T</sub></i> reduced by 25% (light brown bars).</p
Simulations of three parameter pairs with Variant M generated dose-effect curves that describe the relationships between NB synergism and stimulus strength (A), and between additive synergism and stimulus strength (B).
<p>The strength of stimulus (<i>S</i>) was varied from 1 to 40.</p
Summary of the degrees of NB and additive synergism observed for all motifs for <i>S</i> = 1 and <i>S</i> = 10.
<p>Degrees of synergism are plotted for <i>k<sub>dA</sub></i>/<i>k<sub>dB</sub></i> (<b>A</b>), <i>k<sub>dA</sub>/k<sub>ST</sub></i> (<b>B</b>), and <i>k<sub>dA</sub>/K<sub>T</sub></i> (<b>C</b>). Motif abbreviations are as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003524#pcbi-1003524-g001" target="_blank">Fig. 1</a>. Vertical dashed lines delineate each motif and its associated synergism degrees (four for each combination of a motif and a parameter pair). For each motif and parameter pair, the degrees of additive synergism are plotted as blue and light green bars, and the degrees of additive synergism are plotted as black and grey bars, for <i>S</i> = 1 and <i>S</i> = 10 respectively. Negative values represent degrees of antagonism. In a few cases, the NB and AE curves were intertwined (<i>e.g.</i>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003524#pcbi.1003524.s002" target="_blank">Fig. S1B1</a>) and exhibited both additive synergism and additive antagonism. For those cases only positive values (synergism) are plotted. The values of some data are too small to be easily visualized.</p
Facile Approach for the Syntheses of Ultrafine TiO<sub>2</sub> Nanocrystallites with Defects and C Heterojunction for Photocatalytic Water Splitting
In
this paper, a supercritical water (sc-H<sub>2</sub>O) reaction
medium was employed for the syntheses of ultrafine TiO<sub>2</sub> nanocrystallites (at ca. 5 nm) that were linked with lactate species
at surface. The resulting hybrid material was then subjected to an
aging at ca. 300 °C for 2 h under N<sub>2</sub> atmosphere. After
subjected to spherical aberration corrected STEM and EPR analyses,
it was noted that the aged sample was shown with highly distorted
crystal lattice with oxygen vacancies at surface and Ti<sup>3+</sup> in the bulk. The anoxic aging also caused incomplete combustion
for lactate species, leading to the formation of C heterojunction
with TiO<sub>2</sub>. UV–vis, PL and transient photocurrent
(TP) measurements revealed that the resulting surface oxygen vacancies
and C heterojunction had conferred a combination of advantages in
enhancing visible light absorption and promoting electron–hole
pair separation for aged sample, which led to significantly promoted
hydrogen production efficiency in photocatalytic water splitting under
a full-spectrum irradiation (where the aged TiO<sub>2</sub> had yielded
ca. 4-fold higher hydrogen production rate than the nonaged one and
ca. 40–50-fold higher than commercial Degussa P25). We expected
that the work conducted herein could provide a facile and controllable
approach to produce simultaneously defects and C heterojunction for
ultrafine TiO<sub>2</sub> nanocrystallites, which might lead to scale-up
production of them for industry