Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist-induced apoptosis in cardiomyocytes.

The relaxin family peptides have been shown to exert several beneficial effects on the heart, including anti-apoptosis, anti-fibrosis, and anti-hypertrophy activity. Understanding their regulation might provide new opportunities for therapeutic interventions, but the molecular mechanism(s) coordinating relaxin expression in the heart remain largely obscured. Previous work demonstrated a role for the orphan nuclear receptor Nur77 in regulating cardiomyocyte apoptosis. We therefore investigated Nur77 in the hopes of identifying novel relaxin regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) data indicated that ectopic expression of orphan nuclear receptor Nur77 markedly increased the expression of latexin-3 (RLN3), but not relaxin-1 (RLN1), in neonatal rat ventricular cardiomyocytes (NRVMs). Furthermore, we found that the -adrenergic agonist isoproterenol (ISO) markedly stimulated RLN3 expression, and this stimulation was significantly attenuated in Nur77 knockdown cardiomyocytes and Nur77 knockout hearts. We showed that Nur77 significantly increased RLN3 promoter activity via specific binding to the RLN3 promoter, as demonstrated by electrophoretic mobility shift assay (EMSA) and chromatin immuno-precipitation (ChIP) assays. Furthermore, we found that Nur77 overexpression potently inhibited ISO-induced cardiomyocyte apoptosis, whereas this protective effect was significantly attenuated in RLN3 knockdown cardiomyocytes, suggesting that Nur77-induced RLN3 expression is an important mediator for the suppression of cardiomyocyte apoptosis. These findings show that Nur77 regulates RLN3 expression, therefore suppressing apoptosis in the heart, and suggest that activation of Nur77 may represent a useful therapeutic strategy for inhibition of cardiac fibrosis and heart failure. © 2018 You et al

Heterogeneous Graph Neural Network for Privacy-Preserving Recommendation

Social networks are considered to be heterogeneous graph neural networks (HGNNs) with deep learning technological advances. HGNNs, compared to homogeneous data, absorb various aspects of information about individuals in the training stage. That means more information has been covered in the learning result, especially sensitive information. However, the privacy-preserving methods on homogeneous graphs only preserve the same type of node attributes or relationships, which cannot effectively work on heterogeneous graphs due to the complexity. To address this issue, we propose a novel heterogeneous graph neural network privacy-preserving method based on a differential privacy mechanism named HeteDP, which provides a double guarantee on graph features and topology. In particular, we first define a new attack scheme to reveal privacy leakage in the heterogeneous graphs. Specifically, we design a two-stage pipeline framework, which includes the privacy-preserving feature encoder and the heterogeneous link reconstructor with gradients perturbation based on differential privacy to tolerate data diversity and against the attack. To better control the noise and promote model performance, we utilize a bi-level optimization pattern to allocate a suitable privacy budget for the above two modules. Our experiments on four public benchmarks show that the HeteDP method is equipped to resist heterogeneous graph privacy leakage with admirable model generalization

Molecular and physiological basis of Saccharomyces cerevisiae tolerance to adverse lignocellulose-based process conditions

Lignocellulose-based biorefineries have been gaining increasing attention to substitute current petroleum-based refineries. Biomass processing requires a pretreatment step to break lignocellulosic biomass recalcitrant structure, which results in the release of a broad range of microbial inhibitors, mainly weak acids, furans, and phenolic compounds. Saccharomyces cerevisiae is the most commonly used organism for ethanol production; however, it can be severely distressed by these lignocellulose-derived inhibitors, in addition to other challenging conditions, such as pentose sugar utilization and the high temperatures required for an efficient simultaneous saccharification and fermentation step. Therefore, a better understanding of the yeast response and adaptation towards the presence of these multiple stresses is of crucial importance to design strategies to improve yeast robustness and bioconversion capacity from lignocellulosic biomass. This review includes an overview of the main inhibitors derived from diverse raw material resultants from different biomass pretreatments, and describes the main mechanisms of yeast response to their presence, as well as to the presence of stresses imposed by xylose utilization and high-temperature conditions, with a special emphasis on the synergistic effect of multiple inhibitors/stressors. Furthermore, successful cases of tolerance improvement of S. cerevisiae are highlighted, in particular those associated with other process-related physiologically relevant conditions. Decoding the overall yeast response mechanisms will pave the way for the integrated development of sustainable yeast cell--based biorefineries.This study was supported by the Portuguese Foundation for Science and Technology (FCT) by the strategic funding of UID/BIO/04469/2013 unit, MIT Portugal Program (Ph.D. grant PD/BD/128247/ 2016 to Joana T. Cunha), Ph.D. grant SFRH/BD/130739/2017 to Carlos E. Costa, COMPETE 2020 (POCI-01-0145-FEDER-006684), BioTecNorte operation (NORTE-01-0145-FEDER-000004), YeasTempTation (ERA-IB-2-6/0001/2014), and MultiBiorefinery project (POCI-01-0145-FEDER-016403). Funding by the Institute for Bioengineering and Biosciences (IBB) from FCT (UID/BIO/04565/2013) and from Programa Operacional Regional de Lisboa 2020 (Project N. 007317) was also receiveinfo:eu-repo/semantics/publishedVersio

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Optimal Straw Retention Strategies for Low-Carbon Rice Production: 5 Year Results of an In Situ Trial in Eastern China

Crop straw retention in the rice-based rotation cropland has been widely accepted as an effective method to improve soil quality in China. Rice–wheat rotation cropland is one the most prevalent rice-based rotation patterns, where it only exploits a small proportion of the total agricultural land yet feeds the majority of the Chinese population. Previous studies indicated that the incorporation of fore-rotating crop straw can effectively facilitate soil carbon sequestration in rice paddy fields. However, the application of crop straw may increase methane (CH4) emissions from rice paddies due to the anaerobic soil condition. To mitigate CH4 emissions from rice paddies while still preserving their soil carbon sequestration ability, a field experiment was conducted in the 2012–2016 rice growing seasons to determine the optimal low-carbon crop straw retention strategy. Five treatments with different wheat straw retention strategies were employed in this study, including non-fertilization and non-straw (Control), conventional fertilization without straw incorporation (CF), conventional fertilization with wheat straw incorporation (FS), slow-release fertilizer combined with wheat straw (SFS), and conventional fertilization with wheat-straw-derived biochar (FB). The results indicated that FS, SFS, and FB treatments significantly increased soil carbon sequestration in comparison with CF treatment. However, the increment of soil carbon sequestration was offset by raw wheat straw induced excess CH4 emissions under FS and SFS treatments. In contrast, the application of wheat-straw-derived biochar significantly promoted soil carbon sequestration, but showed no significant effect on CH4 emissions. Collectively, to the farmers, who aim to achieve agricultural carbon neutrality, the application of straw-derived biochar is worthy of consideration in rice cultivation processes

Fabrication of thermal energy storage wood based on graphene aerogel encapsulated polyethylene glycol as phase change material

Thermal energy storage wood (TESW) was fabricated by using graphene aerogel encapsulated polyethylene glycol (PEG) as phase change material and wood as the matrix. The microstructure of TESW was investigated by scanning electron microscope (SEM), the thermal properties of TESW was determined by differential scanning calorimetry (DSC), thermal gravimetric analysis (TG) and laser flash diffusivity apparatus (LFA). The results showed that: (1) graphene aerogel (GA) encapsulated PEG composite was founded in the lumens of wood, there was no apparent interface between PEG and graphene aerogel; (2) the melting and freezing enthalpy of TESW were 11.81 and 27.91 J g ^−1 , respectively. The melting and freezing point were 20 °C and 15 °C, respectively, which were suitable for human comfortable temperature; (3) incorporation of graphene aerogel improved the thermal conductivity of TESW apparently. Thermal conductivity of TESW was 0.374 W (m*K) ^−1 , which increased about 274% compared to pure wood; (4) TG and hygroscopicity test indicated that the TESW had excellent thermal and dimensional stability. The TESW was suggested as energy conservation building material for indoor temperature regulating due to its comfortable phase change temperature and prior latent heat