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摘要： The applications of translational modeling of local drug concentrations in various organs had a sharp increase over the last decade. These are part of the model-informed drug development initiative, adopted by the pharmaceutical industry and promoted by drug regulatory agencies. With respect to the kidney, the models serve as a bridge for understanding animal vs. human observations related to renal drug disposition and any consequential adverse effects. However, quantitative data on key drug-metabolizing enzymes and transporters relevant for predicting renal drug disposition are limited. Using targeted and global quantitative proteomics, we determined the abundance of multiple enzymes and transporters in 20 human kidney cortex samples. Nine enzymes and 22 transporters were quantified (8 for the first time in the kidneys). In addition, > 4,000 proteins were identified and used to form an open database. CYP2B6, CYP3A5, and CYP4F2 showed comparable, but generally low expression, whereas UGT1A9 and UGT2B7 levels were the highest. Significant correlation between abundance and activity (measured by mycophenolic acid clearance) was observed for UGT1A9 (Rs = 0.65, P = 0.004) and UGT2B7 (Rs = 0.70, P = 0.023). Expression of P-gp approximate to MATE-1 and OATP4C1 transporters were high. Strong intercorrelations were observed between several transporters (P-gp/MRP4, MRP2/OAT3, and OAT3/OAT4);no correlation in expression was apparent for functionally related transporters (OCT2/MATEs). This study extends our knowledge of pharmacologically relevant proteins in the kidney cortex, with implications on more prudent use of mechanistic kidney models under the general framework of quantitative systems pharmacology and toxicology.

关键词： p-Laplacian operator   Quasilinear elliptic PDE   Critical point and value   Mountain pass theorem   Minimax theorem   Mountain pass type algorithm  

摘要： In this paper, we deal with a specific type of quasilinear boundary value problem with Dirichlet boundary conditions and with p-Laplacian. We show two ways of proving the existence of nontrivial weak solutions. The first one uses the mountain pass theorem, the other one is based on our new minimax theorem. This method is novel even for p = 2. In the paper, we also present a numerical algorithm based on the introduced approach. The suggested algorithm is illustrated on numerical examples and compared with a current approach to demonstrate its efficiency. (C) 2021 International Association for Mathematics and Computers in Simulation (IMACS). Published by Elsevier B.V. All rights reserved.

关键词： Cooperative elliptic systems   p-Laplacian systems   Multiple critical points   Local min-orthogonal method   Finite element method  

摘要： The objective of the present paper is to provide a detailed account of a local min orthogonal method for finding multiple coexisting solutions to cooperative p-Laplacian systems. A local L-perpendicular to selection mapping on a product space of two Banach spaces is introduced in order to develop a local characterization of the coexisting solutions. Using this local characterization we propose a numerical algorithm for finding multiple coexisting solutions to the system and provide a subsequence convergence result of the algorithm. We also discuss the discretization of the problem using the finite element method and the associated convergence results of the numerical solutions. Finally, we provide the numerical results to demonstrate the efficiency of the proposed method and also to confirm its related theoretical results. (C) 2021 IMACS. Published by Elsevier B.V. All rights reserved.

关键词： Trace elements  

摘要： Tuffaceous layers are regularly preserved in Miocene carbonate and siliciclastic sediments of the Dinarides and Eastern Alps in southeastern and central Europe. Detailed mineralogical and geochemical analyses of 13 tuffs of known ages acquired from sedimentary successions of the intramontane Dinarides basins and the southwestern Pannonian Basin were carried out to infer on plausible source areas, relative strengths of volcanism, and ash distribution patterns. Studied tuffs were altered to various degrees with illite-smectite and smectite as dominant phases while volcanic glass, carbonates and other silicates are minor constituents. Tuffs' compositions range from andesite through trachyandesite to rhyolite and trachyte. Trace-element-based correlation with regional data reveal that Lower Miocene (LM) and Lower Middle Miocene (LMM) tuffs (17.0-14.0 Ma) likely originated in the Western Carpathians (the Bukkalja volcanic field) while source areas of Upper Middle Miocene (UMM) tuffs (13.8-12.5 Ma) were in the Apuseni Mountains and/or Eastern Carpathians. The spatial relation of LM/LMM and UMM tuffs with respect to their source areas (the Bukkalja volcanic field and Apuseni Mountains, respectively) is most consistent with tropospheric easterly trade winds that carried ash hundreds of kilometres to the SW toward an azimuth of c. 200-250 degrees.

摘要： Considering that the catastrophe theory could describe quantitatively any phase transition process, we adopt the folding and cusp catastrophe types as the potential functions in the Schrodinger equation to attempt to link the quantum dynamics and the classical wave motions. Thus, through the dimensionless analysis a novel kind of partial differential equations is derived out. When the scaling parameter of the novel equation is equal to the Planck's constant, this equation becomes a detailed time-independent Schrodinger equation, from which Bohr correspondence principle can be found. On the other hand, when the scaling parameter tends to zero, this equation could degenerate to the classical Helmholtz equation. Therefore, this novel kind of equations could describe quantitatively the variation process of the wave functions from the macroscopic level to the quantum size. Copyright (C) 2022 EPLA

关键词： Thermodynamic inequalities   Ground state   Anderson bound   Quantum impurity   Polaron   Bipolaron  

摘要： We prove that for a single-component many-body system at zero temperature the inequality E-int <= PV holds, where E-int is the interaction energy, P is pressure and V is volume. This inequality is proven under rather general assumptions with the use of Anderson-type bound relating ground state energies of systems with different numbers of particles. We also consider adding impurity particles to the system and derive inequalities on the chemical potential of the impurity and binding energy of the bound state of two impurities. (C) 2021 Elsevier B.V. All rights reserved.

关键词： Phenols  

摘要： Gaussian wavepacket methods are becoming popular for the investigation of nonadiabatic molecular dynamics. In the present work, a recently developed efficient algorithm for the Direct Dynamics variational Multi-Configurational Gaussian (DD-vMCG) method has been used to describe the multidimensional photodissociation dynamics of phenol including all degrees of freedom. Full-dimensional quantum dynamic calculations including for the first time six electronic states ((1)pi pi, 1(1)pi pi*, 1(1)pi sigma*, 2(1)pi sigma*, 2(1)pi pi*, 3(1)pi pi*), along with a comparison to an existing analytical 4-state model for the potential energy surfaces are presented. Including the fifth singlet excited state is shown to have a significant effect on the nonadiabatic photodissociation of phenol to the phenoxyl radical and hydrogen atom. State population and flux analysis from the DD-vMCG simulations of phenol provided further insights into the decay mechanism, confirming the idea of rapid relaxation to the ground state through the (1)pi pi/1(1)pi sigma* conical intersection.

关键词： cytotoxicity   hemithioindigo   microtubule dynamics   photopharmacology   photoswitch  

摘要： We report the first cellular application of the emerging near-quantitative photoswitch pyrrole hemithioindigo, by rationally designing photopharmaceutical PHTub inhibitors of the cytoskeletal protein tubulin. PHTubs allow simultaneous visible-light imaging and photoswitching in live cells, delivering cell-precise photomodulation of microtubule dynamics, and photocontrol over cell cycle progression and cell death. This is the first acute use of a hemithioindigo photopharmaceutical for high-spatiotemporal-resolution biological control in live cells. It additionally demonstrates the utility of near-quantitative photoswitches, by enabling a dark-active design to overcome residual background activity during cellular photopatterning. This work opens up new horizons for high-precision microtubule research using PHTubs and shows the cellular applicability of pyrrole hemithioindigo as a valuable scaffold for photocontrol of a range of other biological targets.