‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: towards precision medicine
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Gardeux, Vincent↗
SEARCH · Engineering Papers
Results for “DEREGULATION”
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ERK Oscillation-Dependent Gene Expression Patterns and Deregulation by Stress-Response
Studies were undertaken to determine whether ERK oscillations regulate a unique subset of genes in human keratinocytes and subsequently, whether the p38 stress response inhibits ERK oscillations. A DNA microarray identified many genes that were unique to ERK oscillations, and network reconstruction predicted an important role for the mediator complex subunit 1 (MED1) node in mediating ERK oscillation-dependent gene expression. Increased ERK-dependent phosphorylation of MED1 was observed in oscillating cells compared to non-oscillating counterparts as validation. Treatment of keratinocytes with a p38 inhibitor (SB203580) increased ERK oscillation amplitudes and MED1 and phospho-MED1 protein levels. Bromate is a probable human carcinogen that activates p38. Bromate inhibited ERK oscillations in human keratinocytes and JB6 cells and induced an increase in phospho-p38 and decrease in phospho-MED1 protein levels. Treatment of normal rat kidney cells and primary salivary gland epithelial cells with bromate decreased phospho-MED1 levels in a reversible fashion upon treatment with p38 inhibitors (SB202190; SB203580). Our results indicate that oscillatory behavior in the ERK pathway alters homeostatic gene regulation patterns and that the cellular response to perturbation may manifest differently in oscillating vs non-oscillating cells.
carcinogenesis↗
NPP SCCs Based Deregulation Process Application Case Design with Internal Block Diagram of SysML - 19237
- It will be possible to group the radioactive wastes from the perspectives on Systems, Structures and Components (SSCs). This paper covers systematic approaches for deregulating grouped decommissioning wastes. SSCs decomposition structure, mass flow of decommissioning waste, sequence and storage time estimation method for deregulation, and interrelationship between them are presented. The expected benefit is the ability possibly to apply deregulation process to SSCs because SSCs breakdown structure is connected with mass flow of decommissioning waste, deregulation option, and storage time. This allows for the application of deregulation strategies and processes on SSCs basis and can enhance the rationale and traceability of the waste grouping. The sequence for deregulation reflects the logic of ensuring that radioactive nuclides meet self-disposal criteria and storing or disposing radioactive wastes if not met. (authors)
12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
Effects of the Deregulation on the Concentration of the Brazilian Air Transportation Industry
This paper addresses the effects of the deregulation of the Brazilian air transportation industry in terms of the concentration of the market. We will show some metrics that are commonly used to study the concentration of the industry. This paper uses the Herfindhal- Hirschman Index. This index tends to zero in the competitive scenario, with a large number of small firms, and to one in case of a monopolistic scenario. The paper analyses the dynamics of the concentration of the Brazilian domestic air transportation market, in order to evaluate the effects of deregulation. We conclude that the Brazilian market presents oligopoly characteristics and aspects in its current structure that maintain the market concentrated in spite of the Deregulation measures adopted by the aeronautical authority. Keywords: Herfindhal-Hirschman Index, concentration, Deregulation
Guterres, Marcelo Xavier↗
Sex-specific patterns and deregulation of endocrine pathways in the gene expression profiles of Bangladeshi adults exposed to arsenic contaminated drinking water
Arsenic contamination of drinking water occurs globally and is associated with numerous diseases including skin, lung and bladder cancers, and cardiovascular disease. Recent research indicates that arsenic may be an endocrine disruptor. This study was conducted to evaluate the nature of gene expression changes among males and females exposed to arsenic contaminated water in Bangladesh at high and low doses. Twenty-nine (55% male) Bangladeshi adults with water arsenic exposure ranging from 50 to 1000 μg/L were selected from the Folic Acid Creatinine Trial. RNA was extracted from peripheral blood mononuclear cells for gene expression profiling using Affymetrix 1.0 ST arrays. Differentially expressed genes were assessed between high and low exposure groups for males and females separately and findings were validated using quantitative real-time PCR. There were 534 and 645 differentially expressed genes (p < 0.05) in the peripheral blood mononuclear cells of males and females, respectively, when high and low water arsenic exposure groups were compared. Only 43 genes overlapped between the two sexes, with 29 changing in opposite directions. Despite the difference in gene sets both males and females exhibited common biological changes including deregulation of 17β-hydroxysteroid dehydrogenase enzymes, deregulation of genes downstream of Sp1 (specificity protein 1) transcription factor, and prediction of estrogen receptor alpha as a key hub in cardiovascular networks. Arsenic-exposed adults exhibit sex-specific gene expression profiles that implicate involvement of the endocrine system. Due to arsenic's possible role as an endocrine disruptor, exposure thresholds for arsenic may require different parameters for males and females. - Highlights: • Males and females exhibit unique gene expression changes in response to arsenic. • Only 23 genes are common among the differentially expressed genes for the sexes. • Male and female gene lists exhibit common biological implications. • Both sexes exhibit deregulation of cardiovascular and endocrine pathways.
60 APPLIED LIFE SCIENCES↗
Two-stage dynamic deregulation of metabolism improves process robustness & scalability in engineered E. coli.
Here, we report that two-stage dynamic control improves bioprocess robustness as a result of the dynamic deregulation of central metabolism. Dynamic control is implemented during stationary phase using combinations of CRISPR interference and controlled proteolysis to reduce levels of central metabolic enzymes. Reducing the levels of key enzymes alters metabolite pools resulting in deregulation of the metabolic network. Deregulated networks are less sensitive to environmental conditions improving process robustness. Process robustness in turn leads to predictable scalability, minimizing the need for traditional process optimization. We validate process robustness and scalability of strains and bioprocesses synthesizing the important industrial chemicals alanine, citramalate and xylitol. Predictive high throughput approaches that translate to larger scales are critical for metabolic engineering programs to truly take advantage of the rapidly increasing throughput and decreasing costs of synthetic biology.
59 BASIC BIOLOGICAL SCIENCES↗
Deregulation Impact in Negotiating a New Electrical Contract Between NASA Glenn Research Center at Lewis Field and FirstEnergy Corp., Cleveland, Ohio, USA
The governor of the State of Ohio signed amended substitute Senate bill 3 on July 6, 1999, requiring Ohio's electric industry to change from a monopoly environment to a competitive electric environment for generation services. The start date for competitive retail generation services was set for January 1, 2001. This new deregulation law allowed all Ohioans to choose the supplier of generation service, but the transmission and distribution would remain regulated. It also required electric utilities to unbundle the three main components (generation, transmission, and distribution) and make other changes designed to produce a competitive electric generation market. While deregulation was taking shape, the NASA Glenn Research Center electrical contract with FirstEnergy Corp. of Cleveland, Ohio, was to expire on September 7, 1999. Glenn strategically evaluated and incorporated the impacts of electric deregulation in the negotiations. Glenn and FirstEnergy spent over a year in negotiations until the Glenn utility team and the FirstEnergy negotiating team came to an agreement in the fall of 2000, and a new contract became effective on January 1, 2001.
Quach, Quyen T.↗
HERON as a Tool for LWR Market Interaction in a Deregulated Market
This document reports the development of HERON (Holistic Energy Resource Optimization Network), a newly-developed RAVEN (Risk Analysis Virtual ENvironment) plugin for grid and capacity optimization, to technoeconomic analysis in a deregulated market. A short description of the HERON plugin is provided, and the release process is described. HERON as a plugin enables RAVEN to perform stochastic technoeconomic analysis of grid-energy systems in a generic approach. The primary function of HERON is to generate the complex RAVEN workflows necessary to optimize component capacities under stochastic systems. HERON is capable of analyzing systems with complex components transferring a variety of commodities, including production components and varied markets. HERON is capable of optimizing high-resolution dispatch for such systems and guiding stochastic optimization algorithms in RAVEN for finding optimal component capacities. In particular, this document demonstrates the application of HERON to systems with deregulated markets.
29 ENERGY PLANNING, POLICY, AND ECONOMY↗
Evaluation of Hybrid FPOG Applications in Regulated and Deregulated Markets Using HERON
Recent changes in the U.S. energy market, such as low natural gas prices and increased electricity production for variable renewable energy (VRE) sources, have led to an economic crisis for existing light-water reactor (LWR) nuclear power plants (NPP). Many owners and operators of LWRs have elected to decommission these plants rather than continue using them as consistent sources of clean baseload power. This has led to exploration of various possibilities to increase the economic viability of these units, including market restructuring to monetize benefits LWRs already provide to the grid through ancillary markets, load following and economic dispatch, and possible integration of secondary systems directly to the NPP for production of additional products through technologies such as hydrogen electrolysis or water desalination. Previous studies have considered the technologies associated with these Integrated Energy Systems (IES) activities, and the analysis of markets for these secondary products. To analyze the economic viability of various system configurations including IES, especially given the uncertainty surrounding load demand, electricity prices, and the availability of VRE resources, the stochastic technoeconomic analysis package HERON (Heuristic Energy Resource Optimization Network) was released earlier this year as an extension of the risk analysis framework RAVEN (Risk Analysis Virtual Environment). HERON focuses foremost on making the complex uncertainty quantification analysis tools approachable for energy systems analysts, also providing general dispatch optimization algorithms for those workflows. HERON continues to be improved and tested as a significant part of the IES viability analyses performed in this work. HERON is not a capacity expansion model. To consider market and grid energy system development in a variety of scenarios, HERON is best used in coupling with modelling tools such as US-REGEN, which sacrifice some of the uncertainty analysis and resolution of HERON's modelling for the ability to efficiently predict the change in the grid energy system's profile due to economic drivers over decades. HERON can then use this information to explore the economic viability of introducing changes to the predicted outcomes, such as the introduction of an IES. In this work, experts at EPRI using US-REGEN provide six projection scenarios for use in HERON stochastic technoeconomic analysis (STEA) in considering the options available for increasing LWR economic viability through introduction of a hydrogen-centric IES using a high-temperature steam electrolysis plant (HTSE), hydrogen storage, and a constant-rate contracted hydrogen consumer. The results obtained are differential in nature; they do not report expected profits for any configuration, but rather report on the possible increase in the NPV of a configuration with respect to a baseline no-IES configuration. Due to the uncertainty captured in the variable net load of the systems, there is likewise uncertainty in the mean values reported. We consider this viability both in terms of a regulated market, where the energy producers and IES are owned and operated by single entity, as well as a deregulated market, where the IES chooses its bid for electricity generation and is then dispatched by the grid system operator. Results indicate that for deregulated markets, the inclusion of the IES is often statistically beneficial. This is especially true in policies that are not favorable towards nuclear, as nuclear is less often dispatched and is forced to deal with frequent idle capacity. In the nominal case as well as the case of carbon tax policies, inclusion of the IES clearly benefited the economic performance of the NPP. In the regulated case, however, there was a trend towards minimizing the IES, likely due to the optimal sizing performed by US-REGEN of the NPP within the system as well as the lack of penalty for idle capacity at the NPP in the regulated market analyses.
99 GENERAL AND MISCELLANEOUS↗
Differential antioxidant defense and detoxification mechanisms in photodynamically stressed rice plants treated with the deregulators of porphyrin biosynthesis, 5-aminolevulinic acid and oxyfluorfen
This study focuses on differential molecular mechanisms of antioxidant and detoxification systems in rice plants under two different types of photodynamic stress imposed by porphyrin deregulators, 5-aminolevulinic acid (ALA) and oxyfluorfen (OF). The ALA-treated plants with white necrosis exhibited a greater decrease in photochemical quantum efficiency, F{sub v}/F{sub m}, as well as a greater increase in activity of superoxide dismutase, compared to the OF-treated plants. By contrast, the brown necrosis in OF-treated plants resulted in not only more widely dispersed H{sub 2}O{sub 2} production and greater increases in H{sub 2}O{sub 2}-decomposing enzymes, catalase and peroxidase, but also lower ascorbate redox state. In addition, ALA- and OF-treated plants markedly up-regulated transcript levels of genes involved in detoxification processes including transport and movement, cellular homeostasis, and xenobiotic conjugation, with prominent up-regulation of serine/threonine kinase and chaperone only in ALA-treated plants. Our results demonstrate that different photodynamic stress imposed by ALA and OF developed differential actions of antioxidant enzymes and detoxification. Particularly, detoxification system may play potential roles in plant protection against photodynamic stress imposed by porphyrin deregulators, thereby contributing to alleviation of photodynamic damage. - Highlights: • We employ two different types of photodynamic stress, white and brown necrosis. • We examine molecular mechanisms of antioxidative and detoxification systems. • ALA and OF develop differential actions of antioxidant and detoxification systems. • Coordinated mechanism of antioxidants and detoxification works against toxic ROS. • Detoxification system plays critical roles in protection against photodynamic stress.
60 APPLIED LIFE SCIENCES↗
Combination of ascorbate/epigallocatechin-3-gallate/gemcitabine synergistically induces cell cycle deregulation and apoptosis in mesothelioma cells
Malignant mesothelioma (MMe) is a poor-prognosis tumor in need of innovative therapies. In a previous in vivo study, we showed synergistic anti-MMe properties of the ascorbate/epigallocatechin-3-gallate/gemcitabine combination. We have now focused on the mechanism of action, showing the induction of apoptosis and cell cycle arrest through measurements of caspase 3, intracellular Ca{sup 2+}, annexin V, and DNA content. StellArray™ PCR technology and Western immunoblotting revealed DAPK2-dependent apoptosis, upregulation of cell cycle promoters, downregulation of cell cycle checkpoints and repression of NFκB expression. The complex of data indicates that the mixture is synergistic in inducing cell cycle deregulation and non-inflammatory apoptosis, suggesting its possible use in MMe treatment. - Highlights: • Ascorbate/epigallocathechin-gallate/gemcitabine has been tested on mesothelioma cells • A synergistic mechanism has been shown for cell cycle arrest and apoptosis • PCR-array analysis has revealed the de-regulation of apoptosis and cell cycle genes • Maximum upregulation has been found for the Death-Associated Protein Kinase-2 gene • Data suggest that the mixture could be used as a clinical treatment.
60 APPLIED LIFE SCIENCES↗
Stochastic Optimization and Uncertainty Quantification of Natrium-based Nuclear-Renewable Energy Systems for Flexible Power Applications in Deregulated Markets
Rapid integration of variable renewable energy sources (VRES) has made modeling and stochastic optimization of hybrid energy systems crucial for studying their long-term performance and viability. However, most studies have focused on just historical data, which may be unreliable for capturing short-term fluctuations, rare events, and long-term patterns of energy demand, price, and the variability of renewable energy sources. For this study, optimal synthetic time series models were developed using Wasserstein distance. The models were validated by comparing the key statistical measures against those of the historical data. They were then used to optimize the integrated Natrium-style advanced energy systems and their long-term (30 years) economics. The stochastic model performs bi-level optimization to find the optimal sizes for the balance of plant and thermal energy storage, while also optimizing energy dispatch to achieve the maximum net present value. In studies of two deregulated markets (California ISO and the Electric Reliability Council of Texas), the integrated Natrium-style system performed better in CAISO than in ERCOT, given higher and more consistent electricity prices during peak-demand periods. The potentially enlarged cost associated with the variable operation and maintenance of the TES system also plays a significant role in driving the system sizing, thus its impacts on the system are investigated in detail through comparison against a baseline case. The study also finds that the bi-level optimization results based on stochastic gradient descent closely match the grid search results. The uncertainty quantification of the stochastic signals provides further NPV-related insights and probability distributions for the case studies. The normal standard error of the mean of NPV for the case with and without TES VOM for CAISO were found to be 7.73M (plus-minus sign) 1.09M USD and 104.99M (plus-minus sign) 1.25M USD, respectively based on a 95% confidence. Given the relatively small NPV variance based on 150 samples, the analysis affords the most robust possible prediction of the techno-economic performance of the integrated Natrium-style energy systems.
25 ENERGY STORAGE↗
MicroRNA-203-mediated posttranscriptional deregulation of CPEB4 contributes to colorectal cancer progression
Elevated cytoplasmic polyadenylation element-binding 4 (CPEB4) is aberrantly expressed in several malignant cancers. However, its expression pattern, clinical significance, and biological function in colorectal cancer are still unknown. In this study, we demonstrated that CPEB4 is abundantly overexpressed in colorectal cancers and has the potential to be used for predicting clinical outcomes of colorectal cancer patients. We suppressed CPEB4 expression by small interfering RNA (siRNA) in SW480 and LOVO cells to clarify the role of CPEB4 on the cell apoptosis and proliferation in vitro. Further study revealed that knockdown of CPEB4 decreased the expression of anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL), but enhanced the expression of B-cell lymphoma-2-associated X (Bax). In addition, we indicated that CPEB4 is a novel target of miR-203, a tumor suppressive microRNA. Notably, restoration of CPEB4 in SW480 cells inhibited miR-203-induced apoptosis signaling pathway, which in turn enhanced cell proliferation and suppressed cell apoptosis. Taken together, our findings imply that posttranscriptional deregulation of CPEB4 contributes to the inhibited cell proliferation and the enhanced cell apoptosis in colorectal cancer, and directly targeting CPEB4 by miR-203 might be a novel strategy in colorectal cancer treatment. - Highlights: • CPEB4 is aberrantly expressed in human colorectal cancers. • Knockdown of CPEB4 inhibited colorectal cancer cell proliferation and enhanced apoptosis. • CPEB4 is a direct target of miR-203 and inversely correlates with miR-203 expression. • miR-203 inhibited cell growth and enhanced cell apoptosis in CPEB4 dependent manner. • miR-203 is an upstream regulator of the CPEB4-induced apoptosis pathway.
60 APPLIED LIFE SCIENCES↗
Deregulation of miR-126 expression in colorectal cancer pathogenesis and its clinical significance
In this study, we investigated the expression profiles and clinicopathological significance of miR-126 in large cohort of patients with colorectal cancers as well the cellular repercussions of miR-126 in colon cancer cells along with its targets in-vitro. Down regulation of miR-126 expression was associated with histological subtypes, peri-neural tumour infiltration, microsatellite instability and pathological staging of colorectal cancers (p<0.05). Low miR-126 expression was also associated with poorer survival in patients with colorectal cancer. Analysis of matched tissues from the same patient revealed that approximately 70% of the tested patients had similar levels of expression of miR-126 in primary cancer and cancer metastases in both lymph node and distant metastases. In addition, induced overexpression of miR-126 showed reduced cell proliferation, increased apoptosis and decreased accumulation of cells in the G{sub 0}–G{sub 1} phase of the colon cancer cells. Furthermore, SW480{sup +miR-126} cells showed reduced BCL-2 and increased P53 protein expression. To conclude, deregulation of miR-126 in colorectal cancer at the tissue and cellular levels as well as its correlation with various clinicopathological parameters confirm the cancer suppressive role of miR-126 in colorectal cancer. - Highlights: • Low miR-126 expression was associated with pathological features, MSI and staging. • Low miR-126 expression was associated with poorer patients’ survival in CRC. • Many patients had similar levels of miR-126 expression in primary cancer and cancer metastases. • Induced miR-126 expression reduces cancer proliferation & increases apoptosis. • SW480{sup +miR-126} cells showed reduced BCL-2 and increased P53 protein expression.
60 APPLIED LIFE SCIENCES↗
Deletion of Type I glutamine synthetase deregulates nitrogen metabolism and increases ethanol production in Clostridium thermocellum
Clostridium thermocellum rapidly deconstructs cellulose and ferments resulting hydrolysis products into ethanol and other products, and is thus a promising platform organism for the development of cellulosic biofuel production via consolidated bioprocessing. And while recent metabolic engineering strategies have targeted eliminating canonical fermentation products (acetate, lactate, formate, and H 2 ), C. thermocellum also secretes amino acids, which has limited ethanol yields in engineered strains to approximately 70% of the theoretical maximum. To decrease amino acid secretion, we attempted to reduce ammonium assimilation by deleting the Type I glutamine synthetase (glnA) in C. thermocellum. Deletion of glnA reduced levels of secreted valine and total amino acids by 53% and 44% respectively, and increased ethanol yields by 53%. RNA-seq analysis revealed that genes encoding the RNF-complex were more highly expressed in ΔglnA and may have a role in improving NADH-availability for ethanol production. While a significant up-regulation of genes involved in nitrogen assimilation and urea uptake suggested that deletion of glnA induces a nitrogen starvation response, metabolomic analysis showed an increase in intracellular glutamine and α-ketoglutarate levels indicative of nitrogen-rich conditions. Here, we propose that deletion of glnA causes deregulation of nitrogen metabolism, leading to overexpression of nitrogen metabolism genes and, in turn, elevated glutamine/α-ketoglutarate levels. Here we demonstrate that perturbation of nitrogen assimilation is a promising strategy to redirect flux from the production of nitrogenous compounds toward biofuels in C. thermocellum.
59 BASIC BIOLOGICAL SCIENCES↗
Early nuclear retirements in deregulated U.S. markets: Causes, implications and policy options
Here, electricity prices have fallen significantly since 2008, putting commercial nuclear reactors in the United States under substantial financial pressure. In this market environment driven by persistently low natural gas prices and stagnant electricity demand, we estimate that about two thirds of the 100 GW nuclear capacity are uncompetitive over the next few years under the current trajectory. Among those, 18 GW are retiring or are merchant plants at high risk of retiring prematurely. The potential consequences of the hypothetical withdrawal of 20 GW of nuclear capacity include: 1) a ~3.2% increase in carbon emissions if replaced by gas-fired units or 2) a significant increase in cost if replaced by renewables. Without a carbon price, out-of-the-market payments would be needed to effectively maintain merchant nuclear capacity. Filling the revenue gap would come at a fleet-average cost of 3.5-5.5/ MWh for these plants, which is much lower than the cost of subsidizing wind power. The policy support could take the form of direct zero-emission credits, renewable portfolio standard expansion, or clean capacity market mechanisms. As a last resort, the exercise of a new mothballing status could prevent the irreversible retirement of nuclear power assets.
22 GENERAL STUDIES OF NUCLEAR REACTORS↗
Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells
Thiazolidinediones, specific peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-{gamma}-inhibitor, showed that rosiglitazone acts through both PPAR-{gamma}-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-{gamma}. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPK{alpha} and beclin-1. The autophagy seems to be independent of PPAR-{gamma} activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.
60 APPLIED LIFE SCIENCES↗
Ran GTPase protein promotes human pancreatic cancer proliferation by deregulating the expression of Survivin and cell cycle proteins
Highlights: •Overexpression of Ran in pancreatic cancer was correlated with histological grade. •Downregulation of Ran could induce cell apoptosis and inhibit cell proliferation. •The effects were mediated by cell cycle proteins, Survivin and cleaved Caspase-3. -- Abstract: Ran, a member of the Ras GTPase family, has important roles in nucleocytoplasmic transport. Herein, we detected Ran expression in pancreatic cancer and explored its potential role on tumour progression. Overexpressed Ran in pancreatic cancer tissues was found highly correlated with the histological grade. Downregulation of Ran led to significant suppression of cell proliferation, cell cycle arrest at the G1/S phase and induction of apoptosis. In vivo studies also validated that result. Further studies revealed that those effects were at least partly mediated by the downregulation of Cyclin A, Cyclin D1, Cyclin E, CDK2, CDK4, phospho-Rb and Survivin proteins and up regulation of cleaved Caspase-3.
60 APPLIED LIFE SCIENCES↗