Neural-Network-Biased Genetic Algorithms for Materials Design: Evolutionary Algorithms That Learn

Machine learning has the potential to dramatically accelerate high-throughput approaches to materials design, as demonstrated by successes in biomolecular design and hard materials design. However, in the search for new soft materials exhibiting properties and performance beyond those previously achieved, machine learning approaches are frequently limited by two shortcomings. First, because they are intrinsically interpolative, they are better suited to the optimization of properties within the known range of accessible behavior than to the discovery of new materials with extremal behavior. Second, they require large pre-existing data sets, which are frequently unavailable and prohibitively expensive to produce. Here we describe a new strategy, the neural-network-biased genetic algorithm (NBGA), for combining genetic algorithms, machine learning, and high-throughput computation or experiment to discover materials with extremal properties in the absence of pre-existing data. Within this strategy, predictions from a progressively constructed artificial neural network are employed to bias the evolution of a genetic algorithm, with fitness evaluations performed via direct simulation or experiment. In effect, this strategy gives the evolutionary algorithm the ability to “learn” and draw inferences from its experience to accelerate the evolutionary process. We test this algorithm against several standard optimization problems and polymer design problems and demonstrate that it matches and typically exceeds the efficiency and reproducibility of standard approaches including a direct-evaluation genetic algorithm and a neural-network-evaluated genetic algorithm. The success of this algorithm in a range of test problems indicates that the NBGA provides a robust strategy for employing informatics-accelerated high-throughput methods to accelerate materials design in the absence of pre-existing data

Structure–Photophysical Property Relationship of Conjugated Rod–Coil Block Copolymers in Solutions

Structure–Photophysical Property Relationship of Conjugated Rod–Coil Block Copolymers in Solution

Data_Sheet_1_Enhancing the Anticancer Activity of Antrodia cinnamomea in Hepatocellular Carcinoma Cells via Cocultivation With Ginger: The Impact on Cancer Cell Survival Pathways.PDF

<p>Antrodia cinnamomea (AC) is a medicinal fungal species that has been widely used traditionally in Taiwan for the treatment of diverse health-related conditions including cancer. It possesses potent anti-inflammatory and antioxidant properties in addition to its ability to promote cancer cell death in several human tumors. Our aim was to improve the anticancer activity of AC in hepatocellular carcinoma (HCC) through its cocultivation with ginger aiming at tuning the active ingredients. HCC cell lines, Huh-7 and HepG2 were used to study the in vitro anticancer activity of the ethanolic extracts of AC (EAC) alone or after the cocultivation in presence of ginger (EACG). The results indicated that the cocultivation of AC with ginger significantly induced the production of important triterpenoids and EACG was significantly more potent than EAC in targeting HCC cell lines. EACG effectively inhibited cancer cells growth via the induction of cell cycle arrest at G2/M phase and induction of apoptosis in Huh-7 and HepG2 cells as indicated by MTT assay, cell cycle analysis, Annexin V assay, and the activation of caspase-3. In addition, EACG modulated cyclin proteins expression and mitogen-activated protein kinase (MAPK) signaling pathways in favor of the inhibition of cancer cell survival. Taken together, the current study highlights an evidence that EACG is superior to EAC in targeting cancer cell survival and inducing apoptotic cell death in HCC. These findings support that EACG formula can serve as a potential candidate for HCC adjuvant therapy.</p

GSK3β signaling pathway does not involve in p53 expression through ER stress.

<p>Effects of GSK-3β inhibitor, lithium chloride, on p53 expression in ER stress. MCF-7 cells were incubated 1 µg/ml Brefeldin A with or without lithium chloride as time indicated. The total lysates were subjected to immunoblotting with antibodies against anti-p53, anti-GSK-3β, p-ser⁹-GSK-3β, and α-tubulin.</p

Expression of pre-S2Δ large surface protein increased ER stress and NF-κB, ERK, and Akt phosphorylation in Huh-7 cells.

<p>(A) (B) Cells were maintained in FBS–supplemented DMEM and cell lysates were obtained by RIPA lysis buffer. The cell lysates were determined by Western blotting using antibodies specific for GRP78, NF-κB p65, p-Ser276 p65, p-Ser311 p65, ERK, p-ERK, Akt, p-AKTand β-actin.</p

Induction of p53 expression is regulated at the transcriptional level during ER stress.

<p>(A) Induction of p53 expression by BFA was inhibited by protein synthesis inhibitor cycloheximide in MCF-7 cells. The cells were exposed with 1 μg/ml brefeldin A in the presence of the various concentrations of cycloheximide for 24 hr. The expression of p53 and β-actin were analyzed by Western blotting. (B) The p53 mRNA expression was inhibited by actinomycin D during ER stress. MCF-7 cells were treated 1 μg/ml brefeldin A with or without 20 μg/ml actinomycin D for 24 hr and harvested for total RNA isolation. The mRNA level of p53, GRP78 and GAPDH were determined by RT-PCR. (C) The effect of ER stress on p53 mRNA expression, with MCF-7 cells treated with 1 µg/ml brefeldin A in the dose- and time-dependent manner. The total RNA was isolated and then subjected to RT-PCR analysis. The p53 mRNA expression level was quantified densitometrically. (D) The level of p53 mRNA in response to ER stress was determined by real-time RT-PCR. MCF-7 cells were treated with 1µg/ml brefeldin A or 5 µg/ml tunicamycin for 24 hr and harvested for total RNA isolation. Real-time RT–PCR was performed as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039120#s2" target="_blank">Materials and methods</a>. <i>Columns,</i> mean of three independent experiments; bars, SD (**, <i>P</i><0.01, Student's t test).</p

Signaling of p53 expression by NF-κB during endoplasmic reticulum stress.

<p>Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum induces activation of multiple signaling pathways. Many studies have indicated that activation of IRE1, ATF6, and PERK represents the standard UPR pathways and turns on the expression of many downstream genes such as <i>GRP78</i>. ER stress induced caspase-12/caspase-9/caspase-3, PERK/ATF-4/CHOP, IRE1/Ask1/JNK, and PERK/eIF2α/NF-κB signaling pathways and then those pathways may alter cellular homeostasis by regulating multiple genes, resulting in regulation of cell death or survival. This pathway (indicated by <i>heavy arrows</i>) is demonstrated in this report. We demonstrated that induction of p53 expression is mediated by NF-κB during ER stress.</p

Knockdown of p53 protects cells against BFA-induced cell death.

<p>Down-regulation of p53 expression by p53 RNAi during ER stress. (A) MCF-7 cells were cotransfect with pcDNA3.1/pSuper or pcDNA3.1/pSuper-p53 RNAi plasmid by Lipofectammine 2000. The stable transfectants were selected by G418, and then expression of p53 was analyzed by immunoblotting (upper panel). The cell growth rate of MCF-7, MCF-7-pSuper, MCF-7-pSuper-p53-1, and MCF-7-pSuper-p53-2 cells were performed by MTT assay (lower panel). Furthermore, western blot analyses of the expression levels of p53 in MCF-7 cells were subjected to tunicamycin treatment (lower panel). (B) The morphologic changes after a 48-hour 2.5 µg/ml and 5 µg/ml tunicamycin treatment of MCF-7 cells. The cells were followed by photography under phase-contrast magnification. (C) shRNA-mediated knockdown of p53 protects MCF-7 cells from Tunicamycin- or Brefeldin A-induced cell death. The stable transfectants were incubated with Tunicamycin or Brefeldin A in 10% FBS–supplemented DMEM for 48 hr. Cell viability was measured by the MTT assay. <i>Columns,</i> mean of three independent experiments; bars, SD (*, <i>P</i><0.05; **, <i>P</i><0.01, Student's t test).</p

Increased p53 phosphorylation and activity by ER stress.

<p>(A) Nuclear localization of NF-κB and p53 in response to ER stress in MCF-7 cells. The cells were treated with 1 μg/ml BFA, and the localization of NF-κB and p53 were determined by using immunofluorescence staining. (B) NF-κB and p53 nuclear localization were observed in a time-dependent manner after 0, 6, 12, and 24 h exposure to BFA in MCF-7 cells. The cells were treated with 1 μg/ml brefeldin A as time indicated, and NF-κB subunits in the cytoplasmic and nuclear fractions were analyzed by Western blotting with antibodies against NF-κB subunits p65, p50, c-Rel, and p53. Topoisomerase II and α-tubulin were used as internal markers for nuclear and cytoplasmic proteins. (C) time-dependent effect of BFA on p53 phosphorylation. MCF-7 cells were treated with 1 μg/ml brefeldin A in 10% FBS–supplemented DMEM as time indicated. The total cell lysates subjected to immunoblotting with antibodies against anti-p53, anti-p-ser⁶-p53, anti-p-ser¹⁵-p53, anti-p-ser²⁰-p53, anti-p-ser³⁷-p53, and anti-p-ser⁴⁶-p53. Exposure of MCF-7 cells to 50 J/m2 of UV light served as positive control. (D) ER stress induced transcriptional up-regulation of p53. MCF-7 cells were transfected with reporter vectors encoding firefly luciferase driven by p53 promoter, pp53-TA-Luc plasmid. Transfectants were treated with tunicamycin or Brefeldin A for 24 h. Luciferase activities were normalized to that of cotransfected Renilla luciferase. Columns, mean of three independent experiments; bars, SD (*, <i>P</i><0.05, Student's t test).</p

p53 expression is elevated in response to endoplasmic reticulum stress.

<p>(A) and (B) present the dose- and time- dependent effect of ER stress inducer, tunicamycin and brefeldin A, on p53 expression. MCF-7 Cells were exposed to tunicamycin and brefeldin A in 10% FBS–supplemented DMEM as time and dose indicated. The cell lysates were analyzed by western blotting with antibodies for p53, GRP78, and α-tubulin. The p53 protein expression level was quantified densitometrically. GRP78 served as an ER stress marker. (C) Induction of p53 expression by ER stress in three different cell lines. Hela cells were treated with 5 µg/ml tunicamycin in 10% FBS–supplemented DMEM as time indicated. The cell lysates were analyzed by western blotting with specific antibodies for p53 and β-actin.</p