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101.
102.
Baicheng Mei Yuxing Zhou Kenneth S. Schweizer 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(18)
Understanding in a unified manner the generic and chemically specific aspects of activated dynamics in diverse glass-forming liquids over 14 or more decades in time is a grand challenge in condensed matter physics, physical chemistry, and materials science and engineering. Large families of conceptually distinct models have postulated a causal connection with qualitatively different “order parameters” including various measures of structure, free volume, thermodynamic properties, short or intermediate time dynamics, and mechanical properties. Construction of a predictive theory that covers both the noncooperative and cooperative activated relaxation regimes remains elusive. Here, we test using solely experimental data a recent microscopic dynamical theory prediction that although activated relaxation is a spatially coupled local–nonlocal event with barriers quantified by local pair structure, it can also be understood based on the dimensionless compressibility via an equilibrium statistical mechanics connection between thermodynamics and structure. This prediction is found to be consistent with observations on diverse fragile molecular liquids under isobaric and isochoric conditions and provides a different conceptual view of the global relaxation map. As a corollary, a theoretical basis is established for the structural relaxation time scale growing exponentially with inverse temperature to a high power, consistent with experiments in the deeply supercooled regime. A criterion for the irrelevance of collective elasticity effects is deduced and shown to be consistent with viscous flow in low-fragility inorganic network-forming melts. Finally, implications for relaxation in the equilibrated deep glass state are briefly considered.An enormous number of seemingly orthogonal proposals exist for a fundamental connection between a (typically scalar) structural or excess (configurational) thermodynamic quantity and activated relaxation in supercooled liquids (1–12). High chemical complexity for fragile glass formers which exhibit strongly non-Arrhenius relaxation greatly complicates the formulation of predictive theories. A common generic view (1, 3, 8) is that the structural or alpha relaxation time (and viscosity, inverse diffusivity) evolves with cooling as shown in Fig. 1A. Different dynamical mechanisms in the high-, intermediate-, and low-temperature regimes are often envisioned: noncooperative Arrhenius (∼1 ps to 100 ps), critical power law (∼0.1 ns to 100 ns), and cooperative non-Arrhenius (∼0.1 s to 100 s or beyond), respectively. Typically a causal connection is postulated between the logarithm of the alpha time (an effective barrier in thermal energy units) and a specific “order parameter”: 1) in the structural class (6, 7, 13–17), the intensity of the cage peak of the structure factor S(k), local aspect(s) of the radial distribution function g(r), or specific packing motifs; 2) in the thermodynamics class, various measures of free volume (18, 19), excess entropy (20), configurational entropy (21–25), internal energy and enthalpy (26), or with some arguing for an equilibrium phase transition at an inaccessibly low (high) temperature (density) (23, 27–29); 3) in the short time class, the high-frequency shear modulus (2, 30–32), Debye–Waller factor (33), or amplitude of special vibrational modes (33–35); and 4) in the intermediate time class, the concentration of dilute mobile excitations [e.g., strings (36, 37) or facilitating defects (38)]. Many of the proposed order parameters are hard or impossible to uniquely define and/or experimentally measure. The diverse models often claim to capture relaxation data over limited time windows typically based on fitting but usually fail at low and/or high enough temperature (5).Open in a separate windowFig. 1.Global relaxation map and theoretical picture and key predictions. (A) Three-regime relaxation map (curves) for the alpha time with Arrhenius and strongly non-Arrhenius behaviors separated by a crossover regime perhaps of a critical power law (6) form. The proposed two-regime scenario of ECNLE theory (39–42) is based solely on noncooperative and cooperative activated dynamics (slightly overlapping orange and green regions) with the inverse dimensionless compressibility () as the relevant thermodynamic quantity. The approximately five to six decade range that simulations can probe is indicated. (B) Dynamic free energy for a metastable hard sphere (diameter ) fluid (42) as a function of particle displacement at a high packing fraction of = 0.58. Relevant length and energy scales are indicated. (Inset) Schematic of the core physical idea for the alpha relaxation: hopping on the cage scale coupled with a collective elastic displacement of all particles outside the cage. (C) Main: local cage barrier as a function of inverse dimensionless compressibility for 0.44< <0.61 corresponding to a 16 decade increase of the alpha time (39, 41, 42). The metastable regime begins at ∼ 0.5 where the total barrier is ∼1.5 kBT. (Inset) Total barrier as a function of normalized by its = 0.5 value. The elastic barrier is 1 kBT at ∼ 0.55. Packing fractions are given along the top x-axis.Here we present, using only experimental data, a test of a relationship between activated relaxation, local pair structure, and a specific thermodynamic property predicted by the Elastically Collective Nonlinear Langevin Equation (ECNLE) theory (39–41). The results provide support for the following: 1) the coupled local–nonlocal nature of relaxation deeply connected with collective elasticity, 2) the dimensionless amplitude of thermal density fluctuations, S0, as the relevant (nonexcess) thermodynamic property, 3) a roadmap for organizing relaxation data in S0, not in temperature, space, 4) irrelevance of collective elasticity as the origin for the crossover from fragile to strong glass formers, and 5) an explicit demonstration that a dynamics–thermodynamics correlation can be a noncausal consequence of the causal relation between local pair structure and S0. 相似文献
103.
C. Mundiña de Weilenmann L. Vittone G. de Cingolani A. Mattiazzi 《Basic research in cardiology》1987,82(6):507-516
Summary The relationship between myocardial relaxation and phosphorylation of phospholamban, an intrinsic protein of sarcoplasmic reticulum (SR), was studied in perfused rat hearts beating at constant rate and perfused at constant coronary flow. The positive inotropic effect (increase in developed tension, T, and maximal rate of rise of tension, +
) of 3×10–9 and 3×10–8M isoproterenol (ISO) occurred together, with a proportionately greater increase in maximal velocity of relaxation, –
. Thus, the +
/–
ratio decreased 0.23±0.04 and 0.41±0.05 respectively. Time to half-relaxation (t1/2) and the time constant of relaxation (Tau) were also significantly decreased by ISO. Phospholamban phosphorylation (in pmol32Pi/mg SR protein) increased from 23±3.3 (control) to 42±2.3 (3×10–9M ISO) and to 186±19.3 (3×10–8M ISO). When the negative inotropic action of nifedipine was just offset by either Ca2+ (N–Ca2+) or ISO (N–I), relaxation was faster when ISO was present. Perfusion with N–I significantly decreased +
/–
0.18±0.05, t1/2 14±3 ms and Tau 1.4±0.2 ms. Phospholamban phosphorylation significantly increased from 23±3.3 to 40±4.9 pmol 32 Pi/mg SR protein. N–Ca2+ did not elicit any significant change in these parameters nor in phospholamban phosphorylation. Thus, phospholamban phosphorylation appears closely related to myocardial relaxation and may be one of the important mechanisms by which contractility and relaxation are dissociated in vivo.This work was supported by grants # 3-106600/85 from CONICET and # 2109-1239/85 from CIC. 相似文献
104.
M. Bryhn M.D. 《Clinical cardiology》1984,7(12):639-646
Parameters of left ventricular filling obtained from time-activity curves of radionuclide angiograms were compared with parameters of myocardial relaxation from digitized M-mode curves of the free wall endocardium in 25 consecutive patients. Eight patients had normal left ventricular systolic and diastolic function. Five patients with low ejection fraction (EF < 50%) also had abnormal values of peak filling rate (PFR), time to peak filling rate (Tr), and/or time constant of endocardial retraction (Te). Twelve patients with normal EF had three (40%), two (40%), or one (20%) of the diastolic parameters within the pathological range. Tr correlated significantly with Te (r=0.88, p<0.001), and patients with Te prolongation always had high values of Tr. One of the diastolic parameters (PFR) correlated significantly with EF (r=0.60, p<0.01). Parameters of left ventricular filling and myocardial relaxation are thus abnormal in many patients with normal systolic function, indicating that diastolic parameters may be more sensitive to myocardial deterioration. 相似文献
105.
106.
107.
108.
Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin
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Ryoko Sawamura Hidetaka Sakurai Naoya Wada Yumi Nishiya Tomoyo Honda Miho Kazui Atsushi Kurihara Akira Shinagawa Takashi Izumi 《Biopharmaceutics & drug disposition》2015,36(6):352-363
Loxoprofen (LX) is a prodrug‐type non‐steroidal anti‐inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans‐alcohol form of LX (trans‐OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans‐OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans‐OH form increased in a time‐ and dose‐dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans‐OH form were examined by a mathematical pharmacokinetic model. The Km value was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans‐OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti‐human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the Km and Vmax values were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans‐OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd. 相似文献
109.
AbstractMass spectrometry plays a pivotal role in drug metabolism studies, which are an integral part of drug discovery and development nowadays. Metabolite identification has become critical to understanding the metabolic fate of drug candidates and to aid lead optimization with improved metabolic stability, toxicology and efficacy profiles. Ever since the introduction of atmospheric ionization techniques in the early 1990s, liquid chromatography coupled with mass spectrometry (LC/MS) has secured a central role as the predominant analytical platform for metabolite identification as LC and MS technologies continually advanced. In this review, we discuss the evolution of both MS technology and its applications over the past 50 years to meet the increasing demand of drug metabolism studies. These advances include ionization sources, mass analyzers, a wide range of MS acquisition strategies and data mining tools that have substantially accelerated the metabolite identification process and changed the overall drug metabolism landscape. Exemplary applications for characterization and identification of both small-molecule xenobiotics and biological macromolecules are described. In addition, this review discusses novel MS technologies and applications, including xenobiotic metabolomics that hold additional promise for advancing drug metabolism research, and offers thoughts on remaining challenges in studying the metabolism and disposition of drugs and other xenobiotics. 相似文献
110.
目的 评价放线菌黑色浅灰链霉菌(Streptomyces nigrogriseolus XD 2⁃7)代谢产物储存稳定性及其分离纯化产物实验室杀螺活性,并初步探讨其杀螺作用机制。方法 制备黑色浅灰链霉菌发酵上清液,将其于-20 ℃、4 ℃和28 ℃无光照条件下放置10 d后,测定其72 h浸杀灭螺效果;将发酵上清液置于100 ℃水浴中煮沸30 min后恢复至室温,测定其72 h浸杀灭螺效果;用浓盐酸和氢氧化钠调节发酵上清液pH值为4.0、6.0和9.0,室温下静置12 h,再调节发酵上清液pH至7.0,测定其72 h浸杀灭螺效果。用大孔树脂、硅胶和十八烷基硅烷键合硅胶依次对黑色浅灰链霉菌发酵产物进行4次分离纯化,将最终分离纯化产物配置成10.00、5.00、2.50、1.25 mg/L和0.63 mg/L浓度药液,测定其72 h浸杀灭螺效果。各实验设立空白对照组以脱氯水处理,阳性对照组以0.10 mg/L氯硝柳胺处理。采用高效液相色谱法测定经纯化代谢产物浸泡后钉螺软体组织中三磷酸腺苷(adenosine triphosphate, ATP)和二磷酸腺苷(adenosine diphosphate, ADP)含量。结果 黑色浅灰链霉菌发酵上清液在-20 ℃、4 ℃和28 ℃无光照条件下放置10 d后,原液及稀释10、50倍药液浸杀钉螺72 h,钉螺死亡率均为100.00%(30/30);经100 ℃煮沸30 min后,原液及稀释10、50倍药液浸杀钉螺72 h,钉螺死亡率均为100.00%(30/30)。发酵上清液在pH值为4.0、6.0条件下存储12 h后浸杀钉螺72 h,钉螺死亡率均为100.00%(30/30);在pH值为9.0条件下存储12 h后浸杀钉螺72 h,钉螺死亡率为33.33% (10/30,[χ2] = 30.000,P < 0.05)。发酵上清液最终分离纯化产物100.00%(30/30)杀死钉螺所需最低浓度为1.25 mg/L。以0.10 mg/L和1.00 mg/L浓度最终分离纯化产物处理钉螺后,钉螺软体组织中ATP水平较对照组显著降低(F = 7.274,P < 0.05),ADP水平与对照组差异无统计学意义(F = 2.485,P > 0.05)。结论 黑色浅灰链霉菌代谢产物中杀螺活性成分可在-20 ℃、4 ℃和28 ℃条件下稳定储存10 d,且耐热、耐酸而不耐碱,其杀螺机制可能是使钉螺能量代谢发生紊乱而死亡。 相似文献