Precritical State Transition Dynamics in the Attractor Landscape of a Molecular Interaction Network Underlying Colorectal Tumorigenesis

<div><p>From the perspective of systems science, tumorigenesis can be hypothesized as a critical transition (an abrupt shift from one state to another) between proliferative and apoptotic attractors on the state space of a molecular interaction network, for which an attractor is defined as a stable state to which all initial states ultimately converge, and the region of convergence is called the basin of attraction. Before the critical transition, a cellular state might transit between the basin of attraction for an apoptotic attractor and that for a proliferative attractor due to the noise induced by the inherent stochasticity in molecular interactions. Such a flickering state transition (state transition between the basins of attraction for alternative attractors from the impact of noise) would become more frequent as the cellular state approaches near the boundary of the basin of attraction, which can increase the variation in the estimate of the respective basin size. To investigate this for colorectal tumorigenesis, we have constructed a stochastic Boolean network model of the molecular interaction network that contains an important set of proteins known to be involved in cancer. In particular, we considered 100 representative sequences of 20 gene mutations that drive colorectal tumorigenesis. We investigated the appearance of cancerous cells by examining the basin size of apoptotic, quiescent, and proliferative attractors along with the sequential accumulation of gene mutations during colorectal tumorigenesis. We introduced a measure to detect the flickering state transition as the variation in the estimate of the basin sizes for three-phenotype attractors from the impact of noise. Interestingly, we found that this measure abruptly increases before a cell becomes cancerous during colorectal tumorigenesis in most of the gene mutation sequences under a certain level of stochastic noise. This suggests that a frequent flickering state transition can be a precritical phenomenon of colorectal tumorigenesis.</p></div

The number of sequences for gene mutations that resulted in an M_F greater than the M_FTH.

<p>A: the number of sequences that drove the cancerous state.</p><p>B: the number of sequences that drove the cancerous state and had an M_F greater than the M_FTH.</p><p>C: the number of sequences that did not drive the cancerous state.</p><p>D: the number of sequences that did not drive the cancerous state but had an M_F greater than the M_FTH.</p><p>The number of sequences for gene mutations that resulted in an M_F greater than the M_FTH.</p

Generality of the more frequent flickering state transition before developing into colorectal cancer.

<p>Colorectal tumorigenesis is driven by the sequential accumulation of 20 gene mutations for 100 representative sequences for 20 gene mutations that drive colorectal tumorigenesis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140172#pone.0140172.s003" target="_blank">S1 Table</a>). Zero on the x-axis means no mutation. (a) The frequency distribution of the occurrence point of the cancerous state along with the sequences that drove the cancerous state for the various levels of noise intensity. For the noise intensities of 0, 0.01, 0.02, and 0.03, the cancerous state occurs in 97, 99, 99, and 97 sequences of the 100 sequences, respectively (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140172#pone.0140172.t001" target="_blank">Table 1</a>). (b) The frequency distribution of the M_F greater than the M_FTH at every mutation occurrence along with the sequences that drove the cancerous state for the various levels of noise intensity. We defined the upper threshold of M_F (M_FTH) to investigate whether the flickering state transition becomes more frequent in the attractor landscape. For the noise intensities of 0.01, 0.02, and 0.03, an M_F greater than the M_FTH appears in 46, 80, and 81 sequences of 99, 99, and 97 sequences that drove the cancerous state, respectively (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140172#pone.0140172.t001" target="_blank">Table 1</a>). The y-axis indicates how many sequences among the sequences that drove the cancerous state have an M_F greater than the M_FTH at a particular mutation occurrence.</p

Flickering state transition during colorectal tumorigenesis in the conditions of N_I = 0.03.

<p>Colorectal tumorigenesis is driven by the sequential accumulation of 20 gene mutations (the sequence of No. 73 in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140172#pone.0140172.s003" target="_blank">S1 Table</a>). Zero on the x-axis means no mutation. (a) and (b) the fraction of the initial states converging into the apoptotic, proliferative or quiescent attractors for 320,000 initial states at every gene mutation with N_I = 0 and 0.03, respectively. (c) A graphical representation of M_F (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140172#pone.0140172.e001" target="_blank">Eq (1)</a>) to check the flickering state transition. B_A, B_P, and B_Q represent the fractions of the basin sizes for the apoptotic, proliferative, and quiescent attractors, respectively. B_A0, B_P0, and B_Q0 express the fractions of the basin sizes for the apoptotic, proliferative, and quiescent attractors in the absence of noise, respectively, and B_AN, B_PN, and B_QN are the fraction of the basin sizes for the apoptotic, proliferative, and quiescent attractors in the presence of noise, respectively. (d) M_F at every mutation occurrence for N_I = 0.03, as a result of Fig 2(a) and (b).</p

Flickering state transition before a critical transition in attractor dynamics.

<p>(a) and (b) represent critical transitions without and with noise in the attractor dynamics, respectively. The x-axis represents the effector sequence, and the y-axis denotes the state of the system. A solid line indicates an attractor, and the dotted line between the two solid lines represents an unstable state. A critical transition to an alternative attractor state (A) occurs at a bifurcation point (F1 or F2). Effectors in (a) and (b) are factors changing the attractor landscape. (c), (d), and (e) indicate the attractor landscapes reflecting the stability properties of the system in the region of (X), (Y), and (Z), respectively. Because a potential on the y-axis is inversely related to the steady state probability of its state, the dynamics tends to converge to a state with lower potential. A ball (grey circle) represents the current state and its potential. (d) In the region of (Y), the ball jumps back and forth between alternative basins of attraction from the impact of noise, namely the flickering state transition ((B) in Fig 1(b)). Such a flickering state transition increases the variation in the estimate of the basin sizes (the sizes of the basin of attraction) for the attractors.</p

Quantum Dot/Siloxane Composite Film Exceptionally Stable against Oxidation under Heat and Moisture

We report on the fabrication of a siloxane-encapsulated quantum dot (QD) film (QD-silox film), which exhibits stable emission intensity for over 1 month even at elevated temperature and humidity. QD-silox films are solidified via free radical addition reaction between oligosiloxane resin and ligand molecules on QDs. We prepare the QD-oligosiloxane resin by sol–gel condensation reaction of silane precursors with QDs blended in the precursor solution, forgoing ligand-exchange of QDs. The resulting QD-oligosiloxane resin remains optically clear after 40 days of storage, in contrast to other QD-containing resins which turn turbid and ultimately form sediments. QDs also disperse uniformly in the QD-silox film, whose photoluminescence (PL) quantum yield (QY) remains nearly unaltered under harsh conditions; for example, 85 °C/5% relative humidity (RH), 85 °C/85% RH, strongly acidic, and strongly basic environments for 40 days. The QD-silox film appears to remain equally emissive even after being immersed into boiling water (100 °C). Interestingly, the PL QY of the QD-silox film noticeably increases when the film is exposed to a moist environment, which opens a new, facile avenue to curing dimmed QD-containing films. Given its excellent stability, we envision that the QD-silox film is best suited in display applications, particularly as a PL-type down-conversion layer

Quantum Dot/Siloxane Composite Film Exceptionally Stable against Oxidation under Heat and Moisture

We report on the fabrication of a siloxane-encapsulated quantum dot (QD) film (QD-silox film), which exhibits stable emission intensity for over 1 month even at elevated temperature and humidity. QD-silox films are solidified via free radical addition reaction between oligosiloxane resin and ligand molecules on QDs. We prepare the QD-oligosiloxane resin by sol–gel condensation reaction of silane precursors with QDs blended in the precursor solution, forgoing ligand-exchange of QDs. The resulting QD-oligosiloxane resin remains optically clear after 40 days of storage, in contrast to other QD-containing resins which turn turbid and ultimately form sediments. QDs also disperse uniformly in the QD-silox film, whose photoluminescence (PL) quantum yield (QY) remains nearly unaltered under harsh conditions; for example, 85 °C/5% relative humidity (RH), 85 °C/85% RH, strongly acidic, and strongly basic environments for 40 days. The QD-silox film appears to remain equally emissive even after being immersed into boiling water (100 °C). Interestingly, the PL QY of the QD-silox film noticeably increases when the film is exposed to a moist environment, which opens a new, facile avenue to curing dimmed QD-containing films. Given its excellent stability, we envision that the QD-silox film is best suited in display applications, particularly as a PL-type down-conversion layer

Coproducing Value-Added Chemicals and Hydrogen with Electrocatalytic Glycerol Oxidation Technology: Experimental and Techno-Economic Investigations

The electrocatalytic oxidation technology of biomass-derived oxygenates such as glycerol presents a promising method of coproducing renewable chemicals and hydrogen in an electrochemical reactor system that uses oxidation chemistry and existing proton exchange membrane technology to electrocatalytically convert oxygenates into value-added chemicals and hydrogen. In this paper, we first demonstrate the techno-economic feasibility of the electrocatalytic glycerol oxidation technology with our experimental investigations. Simple and direct conversion of glycerol into glyceraldehyde (GAD), glyceric acid (GLA), and hydroxypyruvic acid (HPA) by anodic oxidation in an electrocatalytic batch reactor over Pt/C catalysts was performed with only water as a stoichiometric chemical oxidant. We also conducted conventional catalytic (non-electrocatalytic) glycerol oxidation using a catalytic batch reactor with pressurized oxygen as the oxidant to compare conventional catalytic performances to that of the electrocatalytic reactor. The electrocatalytic glycerol oxidation process had a yield for GAD, GLA, and HPA production that was ∼1.7 times higher than that of the non-electrocatalytic process. The turnover frequency of the electrocatalytic process is comparable to and even higher than that of a non-electrocatalytic system. On the basis of the experimental results, we develop process simulation models for both the electrocatalytic and non-electrocatalytic processes and then analyze the energy efficiency and economics of the process models. The minimum selling price (MSP) of GLA for the electrocatalytic process was $2.30/kg of GLA compared to$4.91/kg of GLA for the non-electrocatalytic process

Conducting Nanopaper: A Carbon-Free Cathode Platform for Li–O₂ Batteries

For a lithium–oxygen (Li–O₂) battery air electrode, we have developed a new all-in-one platform for designing a porous, carbon-free conducting nanopaper (CNp), which has dual functions as catalyst and current-collector, composed of one-dimensional conductive nanowires bound by a chitin binder. The CNp platform is fabricated by a liquid diffusion-induced crystallization and vacuum filtration methods. Employing less than 1 wt % chitin to connect the conductive skeleton, pores and active sites for reactions have become maximized in self-standing CNp. The carbon-free CNp enables the Li–O₂ air electrode to be more stably operated compared to carbon nanofibers and other CNps bound by PVDF and PMMA; side reactions are largely suppressed on the CNp. The versatile chitin is highlighted for diverse conducting nanopapers that can be used in various applications