Diseases of infection, of neurodegeneration (such as Alzheimer’s and Parkinson’s diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power ...to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists.
Selective weed treatment is a critical step in autonomous crop management as related to crop health and yield. However, a key challenge is reliable and accurate weed detection to minimize damage to ...surrounding plants. In this letter, we present an approach for dense semantic weed classification with multispectral images collected by a micro aerial vehicle (MAV). We use the recently developed encoder-decoder cascaded convolutional neural network, SegNet, that infers dense semantic classes while allowing any number of input image channels and class balancing with our sugar beet and weed datasets. To obtain training datasets, we established an experimental field with varying herbicide levels resulting in field plots containing only either crop or weed, enabling us to use the normalized difference vegetation index as a distinguishable feature for automatic ground truth generation. We train six models with different numbers of input channels and condition (fine tune) it to achieve ~0.8 F1-score and 0.78 area under the curve classification metrics. For the model deployment, an embedded Graphics Processing Unit (GPU) system (Jetson TX2) is tested for MAV integration. Dataset used in this letter is released to support the community and future work.
Although radical cystectomy surgery is the standard-of-care for muscle-invasive bladder cancer, it entails complete removal of the bladder and surrounding organs which leads to substantial loss in ...the quality-of-life of patients. Radiotherapy, which spares the bladder, would be a more appropriate treatment modality if we can utilize molecular markers to select patients with better response to radiation. In this study, we investigate a protein called high mobility group box protein 1 (HMGB1) as a predictive marker for radiotherapy response in bladder cancer. Our in vitro results indicate a positive correlation between higher levels of HMGB1 protein and resistance to radiation in various cell lines. Upon HMGB1 protein knockdown, highly significant (>1.5-fold) sensitization to radiotherapy was achieved. We saw that loss of HMGB1 was associated with at least two times higher (P < 0.001) DNA damage in cell lines postradiation. Our results also depicted that autophagy was inhibited more than 3-fold (P < 0.001) upon HMGB1 knockdown, implicating its role in autophagy as another cause of bladder cancer radioresistance. Further validation was done in vivo by conducting mouse tumor xenograft experiments, where HMGB1 knockdown tumors showed a significantly better (P < 0.001) response to radiotherapy and decreased autophagy (shown by P62 staining) as compared with controls. The cumulative findings of our in vitro and in vivo studies highlight the significance of HMGB1 as a radiation response marker as well as its utility in radiosensitization of bladder cancer.
The electrochemical response of two biologically important benzopyrazine derivative, Quinoxaline and Brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxaline-6-amine) was studied at glassy ...carbon electrode. Investigations were performed in acetate buffer at pH 3.6 where both compounds undergo complex electrode process which begins with quasi reversible redox process at pyrazine ring forming di-hydro derivative, which is further irreversible oxidized to hydroxyl-derivative. Cyclic voltammetry at different scan rates was employed for the determination of heterogeneous electron transfer rate constant and diffusion coefficient of the compounds. The values of electron transfer rate constant at different temperatures were used for the evaluation of thermodynamic parameters like enthalpy, entropy and Gibbs free energy changes, as well as apparent energy of activation.
Computational study has been performed in order to evaluate some useful quantum chemical parameters with the aim to confirm and explain the difference in experimentally obtained kinetic and thermodynamic parameters of the investigated QUI and BRIM redox process. Results were compared with studies of similar compounds and pointed out the observed similarities and differences.
•Redox process of Quinoxaline and Brimonidine at GCE compared to other benzopyrazines.•The effects of scan rate and temperature on the redox process.•Difference in kinetic and thermodynamic parameters of Quinoxaline and Brimonidine redox process.•Computational study for evaluation of quantum chemical parameters.•Theoretical proof of the results obtained experimentally.
Protolytic equilibria and solubility of verapamil were investigated in the presence and in the absence of nonionic surfactant Brij 35 at a constant ionic strength (0.1 mol/L NaCl) and temperature 25 ...°C. In surfactant free media the intrinsic solubility, S 0 = 4.51 × 10–5 mol/L (only the neutral form is present in the solution) and pH-dependent solubility, S (neutral and ionized form in solution) of verapamil were determined. On the basis of the solubility data, the apparent pK a value 9.15 of verapamil was indirectly obtained. In micellar media (10–3 mol/L Brij 35) the solubility of verapamil free base (S 0,s = 2.76 × 10–3 mol/L) and the apparent pK a,s = 6.35, were determined. The shift in the protolytic equilibria (ΔpK a = −2.80) and the increased solubility of verapamil free base (approximately 60 times) caused by Brij 35 point out to specific interactions between verapamil and the inner part of Brij 35 micelles. The most significant changes in distribution of verapamil equilibrium forms were observed at biopharmaceutically important pH 7.4 which potentially indicates interactions with biomolecules in blood plasma.
The acid–base equilibria of six ACE inhibitors (ACEIs), captopril, cilazapril, enalapril, lisinopril, quinapril, and ramipril, were investigated in the presence of micelles of nonionic surfactant ...Brij 35. The p
K
a
values were potentiometrically determined at 25 °C and at a constant ionic strength (0.1 M NaCl). The obtained potentiometric data were evaluated in the computer program Hyperquad. On the basis of the shift in the p
K
a
values (Δp
K
a
) determined in micellar media in relation to the p
K
a
values previously determined in “pure” water, the effect of Brij 35 micelles on ACEIs ionization was estimated. The presence of nonionic Brij 35 micelles caused a shift in the p
K
a
values of all ionizable groups of the investigated ACEIs (Δp
K
a
from − 3.44 to + 1.9) while shifting the protolytic equilibria of both acidic and basic groups toward the molecular form. The Brij 35 micelles expressed the most pronounced effect on the ionization of captopril among the investigated ACEIs and stronger effect on the ionization of amino than on the ionization of carboxyl groups. The obtained results suggest that ionizable functional groups of ACEIs are involved in interactions with palisade layer of nonionic Brij 35 micelles, which potentially can be considered in physiological conditions. Distribution diagrams of the investigated ACEIs equilibrium forms as a function of pH indicate that the change in distribution is most strongly expressed in pH range 4–8, which includes biopharmaceutically important pH values.
Graphical abstract
Unmanned aerial vehicles represent a new frontier in a wide range of monitoring and research applications. To fully leverage their potential, a key challenge is planning missions for efficient data ...acquisition in complex environments. To address this issue, this article introduces a general informative path planning framework for monitoring scenarios using an aerial robot, focusing on problems in which the value of sensor information is unevenly distributed in a target area and unknown a priori. The approach is capable of learning and focusing on regions of interest via adaptation to map either discrete or continuous variables on the terrain using variable-resolution data received from probabilistic sensors. During a mission, the terrain maps built online are used to plan information-rich trajectories in continuous 3-D space by optimizing initial solutions obtained by a coarse grid search. Extensive simulations show that our approach is more efficient than existing methods. We also demonstrate its real-time application on a photorealistic mapping scenario using a publicly available dataset and a proof of concept for an agricultural monitoring task.
The pK a values of ACE inhibitors captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, and zofenopril were determined by potentiometry. Because to the presence ...of single or several ionizable groups (carboxyl, thiol, primary and secondary amino groups) these substances represent acids and ampholytes. Determinations of pK a values were performed at 25 °C and constant ionic strength of 0.1 M (NaCl), in the absence and in the presence of surfactants, anionic sodium dodecyl sulfate (SDS), cationic cetyltrimethyl ammonium bromide (CTAB), and nonionic 4-octylphenol polyethoxylate (TX 100). A computer program Hyperquad was used to derive pK a values from the data obtained by potentiometric titrations. The observed shift of pK a values from +1.90 to −1.54 pK units demonstrated a significant effect of the surfactants on ionization of ACE inhibitors. It has been observed that the carboxyl group was more susceptible to the effect of the above surfactants than the amino group. Also, among the three surfactants employed, SDS expressed the most prominent effect on acid–base equilibria. On the basis of the shifts of pK a values in the presence of the applied surfactants different ACE inhibitor–micelle interactions were suggested.
The acid–base equilibria of rupatadine fumarate were investigated in the absence and the presence of differently charged anionic (sodium dodecyl sulfate), cationic (cetyltrimethylammonium bromide), ...and nonionic (4-octylphenol polyethoxylate) surfactants. The pK a values of rupatadine and fumaric acid were potentiometrically determined at 25 °C and at a constant ionic strength (0.1 M NaCl). The obtained potentiometric data were evaluated with use of the computer program Hyperquad. Ionization in the surfactant-free media was defined, and the effects of surfactants on protolytic equilibria of rupatadine were estimated, based on a shift of the apparent ionization constants determined in micellar solutions against the pK a values in water. The anionic SDS micelles caused an increase in the pK a values of all the rupatadine ionization centers (ΔpK a up to +1.44), while the shift of protolytic equilibria in different directions was observed in the case of the cationic CTAB (ΔpK a from −1.99 to +0.14) and the nonionic TX-100 (ΔpK a from −0.72 to +0.38) micelles. Distribution diagrams of the equilibrium forms as a function of pH indicate that the change in distribution is most strongly expressed in the pH range 4–8 which includes biopharmaceutically important pH values.
PDF
