ABSTRACT
Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering cLogD7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.
Subject(s)
Cytochrome P-450 CYP3A/chemistry , Enzyme Inhibitors/chemistry , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Animals , Binding Sites , Cell Line, Tumor , Cell Membrane Permeability/drug effects , Cell Proliferation/drug effects , Crystallography, X-Ray , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/chemistry , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/toxicity , Dogs , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , Female , Half-Life , Humans , Kinetics , Madin Darby Canine Kidney Cells , Mice , Mice, Nude , Molecular Dynamics Simulation , Neoplasms/drug therapy , Neoplasms/pathology , Nicotinamide Phosphoribosyltransferase/metabolism , Protein Binding , Protein Structure, Tertiary , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Pyrimidines/toxicity , Solubility , Structure-Activity Relationship , Thermodynamics , Transplantation, Heterologous , Water/chemistryABSTRACT
The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Aminopyridines/chemical synthesis , Cytokines/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors , Amides/chemistry , Aminopyridines/chemistry , Aminopyridines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Cells, Cultured , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity RelationshipABSTRACT
The vertical profile of atmospheric temperature is a principal state variable to study atmospheric stability. A lidar system, constructed using a 355 nm Nd:YAG laser transmitter, measures the temperature profile using the rotational Raman technique. In comparison with traditional Raman lidar, the major innovations are the use of a low peak power and high repetition rate laser to achieve eye-safe operation in a compact reliable instrument and the use of an angle tuning filter to select operating wavelengths. We demonstrate the capability of both nighttime and daytime measurements as a step toward a future stand-alone capability for routine measurements of important meteorological properties in the lower atmosphere.
Subject(s)
Environmental Monitoring/instrumentation , Eye/radiation effects , Lasers , Photometry/instrumentation , Radiation Protection/instrumentation , Spectrum Analysis, Raman/instrumentation , Thermography/instrumentation , Atmosphere/analysis , Equipment Design , Humans , Lenses , TemperatureABSTRACT
The stability classification of loess deposits around tunnels is a vital prerequisite for safe construction in underground environment. Due to the fuzziness and randomness of loess physical and mechanical parameters, the stability prediction of loess deposits shows uncertainty. Existing loess deposit stability classification models rarely consider the uncertainty of influencing factors. A novel classification probability model of loess deposits is proposed for the above problems based on Monte Carlo simulation and multi-dimensional normal cloud (MCS-Cloud). Specifically, five loess parameters, including water content, cohesion, internal friction angle, elastic modulus, and Poisson ratio, were selected as predictors for the stability level of loess deposits. The weights of the predictors were obtained through 50 test samples. After acquiring the numerical characteristics of the normal cloud, the stability level can be comprehensively evaluated with the weighted multi-dimensional normal cloud model. The classification model was applied to the loess tunnel in Yan'an, China. The prediction results are in good agreement with practical engineering, denoting the rationality of the weighted multi-dimensional normal cloud. Finally, the stability classification of loess deposits was discussed from the perspective of uncertainty analysis with the application of MCS. Results proved that the MCS-Cloud model is feasible for classifying the stability of loess deposits surrounding tunnels. The obtained classification probability can be used for quantitative risk assessment of loess tunnels.
Subject(s)
Computer Simulation , Uncertainty , China , Monte Carlo Method , Risk AssessmentABSTRACT
Rockburst is one of the major engineering geological disasters of underground engineering. Accurate rockburst intensity level prediction is vital for disaster control during underground tunnel construction. In this work, a hybrid model integrating the back propagation neural network (BPNN) with beetle antennae search algorithm (BAS) has been developed for rockburst prediction. Before model building, 173 groups of rockburst dataset were collected. Six geological parameters are selected as predictors for rockburst, including the maximum tangential stress of the surrounding rock σθ, the uniaxial compressive strength of rock σc, the tensile strength of rock σt, the stress ratio σθ/σc, the rock brittleness ratio σc/σt, and the elastic energy index Wet. After preprocessed by outlier detection and synthetic minority oversampling technique (SMOTE), the new dataset was divided into training and test parts. BAS could optimize the weights and biases of BPNN from the training process. Then the established hybrid model was applied to the test samples with predicted accuracy of 94.3%, proving that the hybrid model has practical value in researching rockburst prediction.
Subject(s)
Disasters , Neural Networks, Computer , Algorithms , Engineering , Compressive StrengthABSTRACT
Engineering site selection is an essential and systematic work in the early engineering construction stage. At present, the subsea tunnel site selection mainly depends on manual experience. There is still a lack of subsea tunnel site selection systems based on environmental impact. This study develops a comprehensive site selection evaluation system based on the analytic hierarchy process (AHP) and fuzzy evaluation method for the subsea tunnel site selection. It is a multi-indicator mathematical model evaluation system. On this basis, the ecological site selection method of the subsea tunnel is further studied, an indicator system for evaluating the environmental carrying capacity of the island is established, and the site selection results of the subsea tunnel based on the environmental indicators are obtained. We compared the site selection results of the two methods. The results show that the conventional method and the ecological site selection method based on environmental indicators can well carry out the site selection of subsea tunnels. The two methods take into account both the overall and local optimum of the subsea tunnel route and organically combine the overall and local objectives. This way provides a reference for the design and construction of the subsea tunnel in the future and points out the direction for the site selection of other large-scale projects with significant environmental impact.
Subject(s)
Conservation of Natural Resources , Models, TheoreticalABSTRACT
Viable biomass production is a key determinant of suitability of antagonistic yeasts as potential biocontrol agents. This study investigated the effects of three metal ions (magnesium, ferrous, and zinc) on biomass production and viability of the antagonistic yeast, Candida diversa. Using response surface methodology to optimize medium components, a maximum biomass was obtained, when the collective Mg2+, Fe2+, and Zn2+ concentrations were adjusted in a minimal mineral (MM) medium. Compared with the unmodified MM, and three ion-deficient MM media, yeast cells cultured in the three ion-modified MM medium exhibited a lower level of cellular oxidative damage, and a higher level of antioxidant enzyme activity. A biocontrol assay indicated that C. diversa grown in the ion-modified MM exhibited the greatest level of control of gray mold on apple fruit. These results provide new information on culture medium optimization to grow yeast antagonists in order to improve biomass production and biocontrol efficacy.
ABSTRACT
As an eco-friendly management method, biological control of postharvest diseases, utilizing antagonistic yeasts, is a research topic receiving considerable attention. Detailed knowledge on the biology of yeast antagonists is crucial when considering their potential application and development as biocontrol products. Changes in the growth form, such as single-cell to pseudohyphae, have been associated with the mode of action in postharvest biocontrol yeasts. In this study, the antagonistic yeast, Candida diversa, reversibly shifted from a single-cell morphology on yeast peptone dextrose (YPD) medium with 2 % agar to a pseudohyphal morphology on YPD with 0.3 % agar. The tolerance of the pseudohyphal form to heat and oxidative stresses, as well as the biocontrol efficacy against Botrytis cinerea on apple and kiwifruit stored at 25 and 4 °C, was significantly higher as compared to the single-cell form. This study provides new information on the ability of C. diversa to change its morphology and the impact of the morphology shift on stress tolerance and biocontrol performance.
Subject(s)
Biological Control Agents/pharmacology , Botrytis/physiology , Candida/cytology , Candida/physiology , Plant Diseases/prevention & control , Stress, Physiological/drug effects , Actinidia/microbiology , Agar/metabolism , Candida/growth & development , Dose-Response Relationship, Drug , Hot Temperature , Malus/microbiology , Oxidative Stress , Plant Diseases/microbiologyABSTRACT
The objective of this study is to develop an innovative close range digital photogrammetry (CRDP) system using the commercial digital SLR cameras to measure and reconstruct the 3D surface of prosthetics and orthotics. This paper describes the instrumentation, techniques and preliminary results of the proposed system. The technique works by taking pictures of the object from multiple view angles. The series of pictures were post-processed via feature point extraction, point match and 3D surface reconstruction. In comparison with the traditional method such as laser scanning, the major advantages of our instrument include the lower cost, compact and easy-to-use hardware, satisfactory measurement accuracy, and significantly less measurement time. Besides its potential applications in prosthetics and orthotics surface measurement, the simple setup and its ease of use will make it suitable for various 3D surface reconstructions.