Osbornebuckley3384

The poor water solubility and bioactivity of drugs can be potentially improved by using suitable nanocarriers. Herein, an economically viable methodology is developed for encapsulation of hydrophobic anticancer agent, curcumin in casein nanoparticles (CasNPs). The successful encapsulation of curcumin was evident from the structural, thermal and spectroscopic analysis of curcumin encapsulated CasNPs (Cur-CasNPs). The CasNPs and Cur-CasNPs samples were lyophilized for their long-term stability and lyophilized powders are found to be stable for more than 6 months at 4-8 °C. From DLS studies, it has been observed that the variation in average size of drug formulations before and after reconstitution were less than 5%. Further, it shows good water-dispersibility, enhanced bioavailability and pH dependent charge conversal feature. Cur-CasNPs showed pH dependent release characteristics with higher at mild acidic environment and enhanced toxicity towards cancer cells (MCF-7) as compared to normal cells (CHO). Moreover, the CasNPs are non-toxic in nature and the developed nanoformulation of drug exhibits substantial cellular internalization and enhanced toxicity towards MCF-7 cells over pure drug, indicating their potential applications.Volume of distribution at steady state (Vss) is an important pharmacokinetic parameter of a drug candidate. In this study, Vss prediction accuracy was evaluated by using (1) seven methods for rat with 56 compounds, (2) four methods for human with 1276 compounds, and (3) four in vivo methods and three Kp (partition coefficient) scalar methods from scaling of three preclinical species with 125 compounds. The results showed that the global QSAR models outperformed the PBPK methods. Tissue fraction unbound (fu,t) method with adipose and muscle also provided high Vss prediction accuracy. Overall, the high performing methods for human Vss prediction are the global QSAR models, Øie-Tozer and equivalency methods from scaling of preclinical species, as well as PBPK methods with Kp scalar from preclinical species. Certain input parameter ranges rendered PBPK models inaccurate due to mass balance issues. These were addressed using appropriate theoretical limit checks. Prediction accuracy of tissue Kp were also examined. The fu,t method predicted Kp values more accurately than the PBPK methods for adipose, heart and muscle. All the methods overpredicted brain Kp and underpredicted liver Kp due to transporter effects. Successful Vss prediction involves strategic integration of in silico, in vitro and in vivo approaches.

The laser-induced choroidal neovascularization (CNV) mouse model, as the most classic animal model of age-related macular degeneration (AMD), has been widely used. We designed a hand-held mouse holder to optimize mouse fixation in the laser-induced CNV modelling process, which was inconvenient until now. This study aimed to evaluate the effectiveness of our in-house hand-held mouse holder design in the laser-induced CNV mouse modelling process.

Six ophthalmic residents were invited to perform laser-induced CNV mouse modelling by hand or using the holder. We compared the learning time of residents and their physical and mental fatigue with the two methods. In addition, we compared the parameters of CNV modelling with two methods by a skilled operator, including the time of photocoagulation, induction rate and uniformity of CNV lesions.

In the learning phase, the average learning time to master the modelling method was significantly shortened by utilizing the holder. The fatigue in the operation process wthe time for photocoagulation, improving the success rate and consistency of laser-induced lesions.The bc1 complex is a proton pump of the mitochondrial electron transport chain which transfers electrons from ubiquinol to cytochrome c. It operates via the modified Q cycle in which the two electrons from oxidation of ubiquinol at the Qo center are bifurcated such that the first electron is passed to Cytc via an iron sulfur center and c1 whereas the second electron is passed across the membrane by bL and bH to reduce ubiquinone at the Qi center. see more Proton pumping occurs because oxidation of ubiquinol at the Qo center releases protons to the P-side and reduction of ubiquinone at the Qi center takes up protons from the N-side. However, the mechanisms which prevent the thermodynamically more favorable short circuit reactions and so ensure precise bifurcation and proton pumping are not known. Here we use statistical thermodynamics to show that reaction steps that originate from high energy states cannot support high flux even when they have large rate constants. We show how the chemistry of ubiquinol oxidation and the structure of the Qo site can result in free energy profiles that naturally suppress flux through the short circuit pathways while allowing high rates of bifurcation. These predictions are confirmed through in-silico simulations using a Markov state model.Cyclic electron flow (CEF) around photosystem I is vital to balancing the photosynthetic energy budget of cyanobacteria and other photosynthetic organisms. The coupling of CEF to proton pumping has long been hypothesized to occur, providing proton motive force (PMF) for the synthesis of ATP with no net cost to [NADPH]. This is thought to occur largely through the activity of NDH-1 complexes, of which cyanobacteria have four with different activities. While a much work has been done to understand the steady-state PMF in both the light and dark, and fluorescent probes have been developed to observe these fluxes in vivo, little has been done to understand the kinetics of these fluxes, particularly with regard to NDH-1 complexes. To monitor the kinetics of proton pumping in Synechocystis sp. PCC 6803, the pH sensitive dye Acridine Orange was used alongside a suite of inhibitors in order to observe light-dependent proton pumping. The assay was demonstrated to measure photosynthetically driven proton pumping and used to measure the rates of proton pumping unimpeded by dark ΔpH. Here, the cyanobacterial NDH-1 complexes are shown to pump a sizable portion of proton flux when CEF-driven and LEF-driven proton pumping rates are observed and compared in mutants lacking some or all NDH-1 complexes. It is also demonstrated that PSII and LEF are responsible for the bulk of light induced proton pumping, though CEF and NDH-1 are capable of generating ~40% of the proton pumping rate when LEF is inactivated.