AKT2 Blocks Nucleus Translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) While Promoting Caspase Activation during Cardiac Ischemia

The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2 − / − ) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known about the mechanism and apoptotic signaling pathway. Here, we show that AKT2 inhibition does not affect the development of cardiomyocytes but increases cell death during cardiomyocyte ischemia. Caspase-dependent apoptosis of both the extrinsic and intrinsic pathway was inactivated in cardiomyocytes with AKT2 inhibition during ischemia, while significant mitochondrial disruption was observed as well as intracytosolic translocation of cytochrome C (Cyto C) together with apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which are proven to conduct DNA degradation in a range of cell death stimuli. Therefore, mitochondria-dependent cell death was investigated and the results suggested that AIF and EndoG nucleus translocation causes cardiomyocyte DNA degradation during ischemia when AKT2 is blocked. These data are the first to show a previous unrecognized function and mechanism of AKT2 in regulating cardiomyocyte survival during ischemia by inducing a unique mitochondrial-dependent DNA degradation pathway when it is inhibited.This work was supported by the National Natural Science Foundation of China, (Grant No. 81500179); the Natural Science Foundation of Jiangsu Province (Grant No. BK20150696); the Fundamental Research Funds for the Central Universities (Grant No. 2015PY005); the National Found for Fostering Talents of Basic Science (NFFTBS) (Grant No. J1310032); the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD); the National High Technology Research and Development Program of China (863 Program, No.2015AA020314); and the National Natural Science Foundation of China (Grant No. 81570696 and No. 31270985); this work is also sponsored by Qing Lan Project

EndoG Links Bnip3-Induced Mitochondrial Damage and Caspase-Independent DNA Fragmentation in Ischemic Cardiomyocytes

Mitochondrial dysfunction, caspase activation and caspase-dependent DNA fragmentation are involved in cell damage in many tissues. However, differentiated cardiomyocytes repress the expression of the canonical apoptotic pathway and their death during ischemia is caspase-independent. The atypical BH3-only protein Bnip3 is involved in the process leading to caspase-independent DNA fragmentation in cardiomyocytes. However, the pathway by which DNA degradation ensues following Bnip3 activation is not resolved. To identify the mechanism involved, we analyzed the interdependence of Bnip3, Nix and EndoG in mitochondrial damage and DNA fragmentation during experimental ischemia in neonatal rat ventricular cardiomyocytes. Our results show that the expression of EndoG and Bnip3 increases in the heart throughout development, while the caspase-dependent machinery is silenced. TUNEL-positive DNA damage, which depends on caspase activity in other cells, is caspase-independent in ischemic cardiomyocytes and ischemia-induced DNA high and low molecular weight fragmentation is blocked by repressing EndoG expression. Ischemia-induced EndoG translocation and DNA degradation are prevented by silencing the expression of Bnip3, but not Nix, or by overexpressing Bcl-xL. These data establish a link between Bnip3 and EndoG-dependent, TUNEL-positive, DNA fragmentation in ischemic cardiomyocytes in the absence of caspases, defining an alternative cell death pathway in postmitotic cells

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer : development of a prognostic model through a crowdsourced challenge with open clinical trial data

Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0.791; Bayes factor >5) and surpassed the reference model (iAUC 0.743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3.32, 95% CI 2.39-4.62, p Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer.Peer reviewe

Identification and Shape Analysis of Arabidopsis Cultivated in Nitrogen-free Environment

This paper presents a method for segmentation and shape description of Arabidopsis plants with non-green leaves. The image was first calibrated by detecting the corners of a checkerboard. After the preprocessing step, the image was transformed to CIELUV color space, removing the lightness from the chromatic coordinates. The U component showed markedly different textures between the plant and the background. Hence its standard derivation was calculated and thresholded. With this method, significant leaves of the plant were separated while some stalks were not. Therefore, Support Vector Machine was then used to train the LUV data to do further segmentation as a complement of texture analysis. With these two steps, the plant was completely identified and the shape features were then extracted, including the total area, the symmetry and the number of leaves. The real area of the plant was derived with the number of foreground pixels and the calibration result. The symmetries were represented with the degrees of bilateral symmetry in the direction of the major and minor axes. And the number of leaves was obtained by identifying the number of local maximum of the contour-based signature. Experiment result shows that this method is effective in segmentation and shape analysis of Arabidopsis plants

IL-6: A Potential Role in Cardiac Metabolic Homeostasis

Interleukin-6 (IL-6) is implicated in multiple biological functions including immunity, neural development, and haematopoiesis. Recently, mounting evidence indicates that IL-6 plays a key role in metabolism, especially lipid metabolic homeostasis. A working heart requires a high and constant energy input which is largely generated by fatty acid (FA) β-oxidation. Under pathological conditions, the precise balance between cardiac FA uptake and metabolism is perturbed so that excessive FA is accumulated, thereby predisposing to myocardial dysfunction (cardiac lipotoxicity). In this review, we summarize the current evidence that suggests the involvement of IL-6 in lipid metabolism. Cardiac metabolic features and consequences of myocardial lipotoxicity are also briefly analyzed. Finally, the roles of IL-6 in cardiac FA uptake (i.e., serum lipid profile and myocardial FA transporters) and FA metabolism (namely, β-oxidation, mitochondrial function, biogenesis, and FA de novo synthesis) are discussed. Overall, understanding how IL-6 transmits signals to affect lipid metabolism in the heart might allow for development of better clinical therapies for obesity-associated cardiac lipotoxicity

Insertion of NiO electron blocking layer in fabrication of GaN-organic heterostructures

We report the fabrication of a NiO thin film on top of an n-type GaN epitaxial layer. The electron-blocking capability of NiO in a hybrid organic/inorganic heterostructure consisting of n-GaN/NiO/poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (PEDOT: PSS) is discussed. Surface morphology, crystallography orientation, bandgap, and fermi level information of NiO films were investigated in detail. A rectifying property consistent with the proposed band diagram was observed in the current-voltage measurement. Theoretical analysis also demonstrated the effective electron blocking due to band alignment and a more balanced carrier distribution inside the GaN region with NiO inserted into the n-GaN/PEDOT: PSS heterostructure. This work provides a promising approach to the fabrication of high-efficiency hybrid optoelectronic devices. (C) 2018 The Japan Society of Applied Physic

Structural Evolution and Transitions of Mechanisms in Creep Deformation of Nanocrystalline FeCrAl Alloys

FeCrAl alloys have been suggested as one of the most promising fuel cladding materials for the development of accident tolerance fuel. Creep is one of the important mechanical properties of the FeCrAl alloys used as fuel claddings under high temperature conditions. This work aims to elucidate the deformation feature and underlying mechanism during the creep process of nanocrystalline FeCrAl alloys using atomistic simulations. The creep curves at different conditions are simulated for FeCrAl alloys with grain sizes (GS) of 5.6–40 nm, and the dependence of creep on temperature, stress and GS are analyzed. The transitions of the mechanisms are analyzed by stress and GS exponents firstly, and further checked not only from microstructural evidence, but also from a vital comparison of activation energies for creep and diffusion. Under low stress conditions, grain boundary (GB) diffusion contributes more to the overall creep deformation than lattice diffusion does for the alloy with small GSs. However, for the alloy with larger GSs, lattice diffusion controls creep. Additionally, a high temperature helps the transition of diffusional creep from the GB to the dominant lattice. Under medium- and high-stress conditions, GB slip and dislocation motion begin to control the creep mechanism. The amount of GB slip increases with the temperature, or decreases with GS. GS and temperature also have an impact on the dislocation behavior. The higher the temperature or the smaller the GS is, the smaller the stress at which the dislocation motion begins to affect creep