Tissue factor/FVIIa activates Bcl-2 and prevents doxorubicin-induced apoptosis in neuroblastoma cells

<p>Abstract</p> <p>Background</p> <p>Tissue factor (TF) is a transmembrane protein that acts as a receptor for activated coagulation factor VII (FVIIa), initiating the coagulation cascade. Recent studies demonstrate that expression of tumor-derived TF also mediates intracellular signaling relevant to tumor growth and apoptosis. Our present study investigates the possible mechanism by which the interaction between TF and FVIIa regulates chemotherapy resistance in neuroblastoma cell lines.</p> <p>Methods</p> <p>Gene and siRNA transfection was used to enforce TF expression in a TF-negative neuroblastoma cell line and to silence endogenous TF expression in a TF-overexpressing neuroblastoma line, respectively. The expression of TF, Bcl-2, STAT5, and Akt as well as the phosphorylation of STAT5 and Akt in gene transfected cells or cells treated with JAK inhibitor and LY294002 were determined by Western blot assay. Tumor cell growth was determined by a clonogenic assay. Cytotoxic and apoptotic effect of doxorubicin on neuroblastoma cell lines was analyzed by WST assay and annexin-V staining (by flow cytometry) respectively.</p> <p>Results</p> <p>Enforced expression of TF in a TF-negative neuroblastoma cell line in the presence of FVIIa induced upregulation of Bcl-2, leading to resistance to doxorubicin. Conversely, inhibition of endogenous TF expression in a TF-overexpressing neuroblastoma cell line using siRNA resulted in down-regulation of Bcl-2 and sensitization to doxorubicin-induced apoptosis. Additionally, neuroblastoma cells expressing high levels of either endogenous or transfected TF treated with FVIIa readily phosphorylated STAT5 and Akt. Using selective pharmacologic inhibitors, we demonstrated that JAK inhibitor I, but not the PI3K inhibitor LY294002, blocked the TF/FVIIa-induced upregulation of Bcl-2.</p> <p>Conclusion</p> <p>This study shows that in neuroblastoma cell lines overexpressed TF ligated with FVIIa produced upregulation of Bcl-2 expression through the JAK/STAT5 signaling pathway, resulting in resistance to apoptosis. We surmise that this TF-FVIIa pathway may contribute, at least in part, to chemotherapy resistance in neuroblastoma.</p

Genesis of Cambrian Dolomites in the Bachu Area, Tarim Basin, <b>NW China: Constraints from Petrology, Geochemistry, and Fluid Inclusions</b>

The dolomitization of carbonate rocks has always been a hot topic in the study of the dolomite reservoir. In this study, the genesis of Cambrian dolomite in the Bachu area, Tarim Basin, was assessed through petrographic examinations, isotope compositions (C, O, and Sr), trace and rare earth elements, and fluid inclusion microthermometry. Microscopic analysis revealed three types of dolomites: very fine-crystalline, nonplanar dolomite (D1); fine-crystalline, nonplanar to planar-s dolomite (D2); and medium- to coarse-crystalline, planar-e to planar-s dolomite (D3). D1 dolomite exhibits well-preserved original sedimentary features, such as algal laminae, stromatolite, and evaporite streak, and is characterized by the 87Sr/86Sr value and δ18O value in equilibrium with the coeval seawater, its high Sr and Na content, and its low Mn content. This indicates that D1 dolomite is primarily a penecontemporaneous dolomite in tidal flat or lagoon environments, and its dolomitizing fluid is mainly evaporated mesosaline to penesaline seawater. D2 dolomite shows ghosts of precursor particles; features δ13C values in equilibrium with the coeval seawater, high 87Sr/86Sr values, low Sr content, and positive Eu anomaly; and is widely distributed close to stylolite. This illustrates that D2 dolomite was principally formed by seepage–reflux dolomitization, and is closely related to hydrothermal activity and pressure dissolution. D3 dolomite displays a crystal texture with a cloudy core and compositional zoning, and the original sedimentary fabrics cannot be identified. It has similar δ13C values and REE patterns to the calcite precipitated from coeval seawater, high 87Sr/86Sr values, low Sr contents and high Mn/Sr ratios, which suggests that D3 dolomite is chiefly related to the recrystallization of the precursor dolomite during the deep burial stage, and the deep circular brine provides Mg ions through the fluid–rock reaction. This study shows that the Cambrian dolomite in the Bachu area is mainly formed in the coeval seawater environment during the penecontemporaneous and shallow burial stages, and has extensively suffered from recrystallization and burial diagenesis due to long-term deep burial, which was further strengthened in the fracture-enriched area

Effet des bassins de rétention sur les micropolluants des eaux pluviales en ville

Éléments du réseau d’assainissement pluvial, les bassins de rétention en eau sont conçus pour limiter le risque d'inondation dans les bassins versants urbains. Ces bassins peuvent avoir un effet sur les micropolluants présents dans l’eau, en raison notamment de la longueur du temps de séjour de l’eau et de la présence de phytoplancton. C’est pourquoi nous nous sommes intéressés à l’effet du bassin de rétention en eau de Savigny, situé à Aulnay-Sous-Bois (93), sur les micropolluants métalliques apportés par les eaux pluviales. Pour cela nous avons étudié le fonctionnement hydrologique du bassin. Nous avons mis en place et réalisé des campagnes de mesures afin de permettre ultérieurement le bilan des flux de micropolluants métalliques à l’échelle d’un évènement pluvieux.Deux campagnes de temps sec ont servi de référence. Quatre campagnes de temps de pluie ont ensuite été réalisées. De plus, la mise en place d’un préleveur automatique au niveau de la zone d’arrivée des eaux pluviales nous a permis de caractériser les flux entrants et sortants du bassin deSavigny. Dans le bassin de Savigny, qui s’est avéré eutrophe, les variables environnementales indiquent une meilleure qualité dans la partie la plus éloignée de la zone d’arrivée des eaux pluviales, ceci serait dû à un long temps de séjour permettant une bonne sédimentation et à la présence duphytoplancton. Les concentrations de sept métaux, cadmium, chrome, cobalt, cuivre, nickel, plomb et zinc, ont été mesurés dans le bassin de Savigny et dans le ru du Sausset qui l’alimente. Les concentrations des métaux totaux et dissous ainsi que de la fraction inerte qui donne accès à uneévaluation de la biodisponibilité des métaux ont été analysées. Les résultats obtenus montrent que la majorité des concentrations métalliques sont inférieures dans le bassin par rapport à la rivière, même pour la fraction dissoute. La biodisponibilité des métaux est également plus faible dans lebassin que dans la rivière. En raison de leur impact sur l’état écologique et chimique des milieux aquatiques, les concentrations des formes dissoutes de ces métaux font l’objet de normes de qualité environnementale (NQE) dans le cadre de la Directive Cadre sur l’eau. Dans le ru du Sausset et le bassin, les concentrations mesurées sont inférieures aux NQE pour le chrome, le plomb et le cadmium. Les concentrations en cobalt dissous sont proches de la norme. Pour le cuivre la NQE (1.4µg/L) est largement dépassée dans le Sausset, mais elle est respectée dans la majorité des mesures aux points aval et centre du bassin de Savigny. Pour le zinc, la norme est largement dépassée dans toutes les mesures dans le Sausset et respectée dans la plupart des mesures dans le bassin. Néanmoins, pour les deux métaux qui dépassent les NQE, le cuivre et le zinc, une forte réduction de leurs concentrations apparait entre la rivière et le bassin.Ces résultats montrent le rôle positif du bassin de rétention sur la réduction des concentrations en métaux totaux, mais aussi, ce qui est rarement mis en évidence sur les milieux aquatiques urbains, ils mettent en évidence la réduction de la concentration des formes dissoutes et de la fraction la plus biodisponible des métaux

Versatile Molecular Editing via Multimodal and Group-optimized Generative Learning

Generating molecules with specific constituents and structures that exhibit desired properties is a crucial yet challenging task in the computer-aided design of functional molecules. This challenge arises from the discrete nature of the vast design space of molecules, which is subject to additional physical constraints such as symmetries. Exploration and optimization within this constrained discrete space pose difficulties for most machine learning methods. In this paper, we introduce a multimodal representation for molecules that accounts for both their discrete atomic constituents and their continuous atomic positions in 3D Euclidean space. Based on this representation, we develop MolEdit, a molecular generation method that simultaneously solves discrete and continuous optimization problems: MolEdit learns the distribution of molecular constituents using efficient normalizing flow models and employs a group-optimized score matching algorithm to model the symmetry-preserved distribution of atomic positions. By combining these two components, MolEdit can effectively assemble any discrete molecular graph and generate corresponding molecular conformers. Furthermore, by decomposing the generation process multimodally, MolEdit can work with flexible prompts specifying conditional information about molecular constituents and substructures, leading to a general-purpose approach to versatile molecular editing

THOR, Trace-based Hardware-driven Layer-Oriented Natural Gradient Descent Computation

It is well-known that second-order optimizer can accelerate the training of deep neural networks, however, the huge computation cost of second-order optimization makes it impractical to apply in real practice. In order to reduce the cost, many methods have been proposed to approximate a second-order matrix. Inspired by KFAC, we propose a novel Trace-based Hardware-driven layer-ORiented Natural Gradient Descent Computation method, called THOR, to make the second-order optimization applicable in the real application models. Specifically, we gradually increase the update interval and use the matrix trace to determine which blocks of Fisher Information Matrix (FIM) need to be updated. Moreover, by resorting the power of hardware, we have designed a Hardware-driven approximation method for computing FIM to achieve better performance. To demonstrate the effectiveness of THOR, we have conducted extensive experiments. The results show that training ResNet-50 on ImageNet with THOR only takes 66.7 minutes to achieve a top-1 accuracy of 75.9 % under an 8 Ascend 910 environment with MindSpore, a new deep learning computing framework. Moreover, with more computational resources, THOR can only takes 2.7 minutes to 75.9 % with 256 Ascend 910