The success of chemotherapy in cancer treatment is limited by scarce drug delivery to the tumor and severe side-toxicity. Prolyl hydroxylase domain protein 2 (PHD2) is an oxygen/redox-sensitive ...enzyme that induces cellular adaptations to stress conditions. Reduced activity of PHD2 in endothelial cells normalizes tumor vessels and enhances perfusion. Here, we show that tumor vessel normalization by genetic inactivation of Phd2 increases the delivery of chemotherapeutics to the tumor and, hence, their antitumor and antimetastatic effect, regardless of combined inhibition of Phd2 in cancer cells. In response to chemotherapy-induced oxidative stress, pharmacological inhibition or genetic inactivation of Phd2 enhances a hypoxia-inducible transcription factor (HIF)-mediated detoxification program in healthy organs, which prevents oxidative damage, organ failure, and tissue demise. Altogether, our study discloses alternative strategies for chemotherapy optimization.
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► Combined loss of Phd2 in stromal and cancer cells sensitizes tumors to chemotherapy ► Loss of Phd2 protects healthy organs against chemotherapy-induced oxidative damage ► Loss of Phd2 in healthy organs unleashes a HIF-mediated anti-oxidative response
Highlights ► Evaluation of a MOMP-based Chlamydia trachomatis DNA vaccine in a pig model. ► Comparing mucosal and parenteral administration of the vaccine. ► Significant protection against a C. ...trachomatis infection was induced by mucosal vaccination. ► Parenteral immunization did not lead to significant protection.
Highlights * Evaluation of a MOMP-basedChlamydia trachomatisDNA vaccine in a pig model. * Comparing mucosal and parenteral administration of the vaccine. * Significant protection against aC. ...trachomatisinfection was induced by mucosal vaccination. * Parenteral immunization did not lead to significant protection.
Environmental air monitoring is of great interest due to the large number of people concerned and exposed to different possible risks. From the most common particles in our environment (e.g. ...by-products of combustion or pollens) to more specific and dangerous agents (e.g. pathogenic micro-organisms), there are a large range of particles that need to be controlled. In this article we propose an original study on the collection of electrostatically deposited particles using electrowetting droplet displacement. A variety of particles were studied, from synthetic particles (e.g. Polystyrene Latex (PSL) microsphere) to different classes of biological particle (proteins, bacterial spores and a viral simulant). Furthermore, we have compared ElectroWetting-On-Dielectric (EWOD) collecting efficiency using either a hydrophobic or a superhydrophobic counter electrode. We observe different cleaning efficiencies, depending on the hydrophobicity of the substrate (varying from 45% to 99%). Superhydrophobic surfaces show the best cleaning efficiency with water droplets for all investigated particles (MS2 bacteriophage, BG (Bacillus atrophaeus) spores, OA (ovalbumin) proteins, and PSL).
In any region affected, fires exhibit a strong seasonal cycle driven by the dynamic of fuel moisture and ignition sources throughout the year. In this paper we investigate the global patterns of fire ...seasonality, which we relate to climatic, anthropogenic, land-cover and land-use variables. Global, with detailed analyses from single 1°x 1° grid cells. We use a fire risk index, the Chandler burning index (CBI), as an indicator of the 'natural', eco-climatic fire seasonality, across all types of ecosystems. A simple metric, the middle of the fire season, is computed from both gridded CBI data and satellite-derived fire detections. We then interpret the difference between the eco-climatic and observed metrics as an indicator of the human footprint on fire seasonality. Deforestation, shifting cultivation, cropland production or tropical savanna fires are associated with specific timings due to land-use practices, sometimes largely decoupled from the CBI dynamics. Detailed time series from relevant locations provide comprehensive information about these practices and how they are adapted to eco-climatic conditions. We find a great influence of anthropogenic activities on global patterns of fire seasonality. The specificity of the main fire practices and their easy identification from global observation is a potential tool to support land-use monitoring efforts. Our results should also prove valuable in the development of a methodological approach for improving the representation of anthropogenic fire practices in dynamic global vegetation models.
An easy and environmentally friendly chemical method for the simultaneous reduction and noncovalent functionalization of graphene oxide (GO) using dopamine derivatives is described. The reaction ...takes place at room temperature under ultrasonication of an aqueous suspension of GO and a dopamine derivative. X-ray photoelectron spectroscopy, FT-IR spectroscopy, and cyclic voltammetry characterizations revealed that the resulting material consists of graphene functionalized with the dopamine derivative. This one-step protocol is applied for simultaneous reduction and functionalization of graphene oxide with a dopamine derivative bearing an azide function. The chemical reactivity of the azide function was demonstrated by a postfunctionalization with ethynylferrocene using the Cu(I) catalyzed 1,3-dipolar cyloaddition.
Abnormal branched-chained amino acids (BCAA) accumulation in cardiomyocytes is associated with cardiac remodeling in heart failure. Administration of branched-chain α-keto acid dehydrogenase (BCKD) ...kinase inhibitor BT2 has been shown to reduce cardiac BCAA levels and demonstrated positive effects on cardiac function in a preclinical setting. The current study is focused on evaluating the impact of BT2 on the systemic and cardiac levels of BCAA and their metabolites as well as activities of BCAA catabolic enzymes using a quantitative systems pharmacology model.
The model is composed of an ordinary differential equation system characterizing BCAA consumption with food, disposal in the proteins, reversible branched-chain-amino-acid aminotransferase (BCAT)-mediated transamination to branched-chain keto-acids (BCKA), followed by BCKD-mediated oxidation. Activity of BCKD is regulated by the balance of BCKDK and protein phosphatase 2Cm (PP2Cm) activities, affected by BT2 treatment. Cardiac BCAA levels are assumed to directly affect left ventricular ejection fraction (LVEF). Biochemical characteristics of the enzymes are taken from the public domains, while plasma and cardiac BCAA and BCKA levels in BT2 treated mice are used to inform the model parameters.
The model provides adequate reproduction of the experimental data and predicts synchronous BCAA responses in the systemic and cardiac space, dictated by rapid BCAA equilibration between the tissues. The model-based simulations indicate maximum possible effect of BT2 treatment on BCAA reduction to be 40% corresponding to 12% increase in LVEF. Model sensitivity analysis demonstrates strong impact of BCKDK and PP2Cm activities as well as total BCKD and co-substrate levels (glutamate, ketoglutarate and ATP) on BCAA and BCKA levels.
Model based simulations confirms using of plasma measurements as a marker of cardiac BCAA changes under BCKDK inhibition. The proposed model can be used for optimization of preclinical study design for novel compounds targeting BCAA catabolism.
A one-step method for the reduction of graphene oxide (GO) to reduced graphene oxide (rGO) is reported taking advantage of the electron-donor properties of an azido-terminated tetrathiafulvalene ...(TTF-N3). The resulting graphene/TTF-N3 nanohybrid material is characterized by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR) spectroscopy, and by electrical and electrochemical means. The accessibility of the azide function to chemoselective modification by any alkyne-terminated partner molecule via Cu(I)-catalyzed “click” chemistry is demonstrated. In a proof of principle and motivated by the importance of glycan-modified materials, many alkynyl-terminated mannose units were grated onto graphene/TTF-N3. The TTF-mannose units could be released efficiently from the graphene matrix by chemical oxidation of TTF-mannose surface units to TTF2+-mannose, using Fe(ClO4)3 or the electron-deficient tetracationic cyclophane cyclobis(paraquat-p-phenylene) (CBPQT4+).
Nanostructured boron-doped diamond has been investigated as a sensitive impedimetric electrode for the detection of immunoglobulin G (IgG). The immunosensor was constructed in a three-step process: ...(i) reactive ion etching of flat boron-doped diamond (BDD) interfaces to synthesize BDD nanowires (BDD NWs), (ii) electrochemical deposition of nickel nanoparticles (Ni NPs) on the BDD NWs, and (iii) immobilization of biotin-tagged anti-IgG onto the Ni NPs. Electrochemical impedance spectroscopy (EIS) was used to follow the binding of IgG at different concentrations without the use of any additional label. A detection limit of 0.3 ng mL(-1) (2 nM) with a dynamic range up to 300 ng mL(-1) (2 μM) was obtained with the interface. Moreover, the study demonstrated that this immunosensor exhibits good stability over time and allows regeneration by incubation in ethylenediaminetetraacetic acid (EDTA) aqueous solution.
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