AcrA/AcrB/TolCの多剤排出機構に関する統計力学的研究

京都大学0048新制・課程博士博士(エネルギー科学)甲第19092号エネ博第316号新制||エネ||64(附属図書館)32043京都大学大学院エネルギー科学研究科エネルギー基礎科学専攻(主査)教授 木下 正弘, 教授 森井 孝, 教授 片平 正人学位規則第4条第1項該当Doctor of Energy ScienceKyoto UniversityDFA

On the physics of multidrug efflux through a biomolecular complex.

Insertion and release of a solute into and from a vessel comprising biopolymers is a fundamental function in a biological system. A typical example is found in a multidrug efflux transporter. "Multidrug efflux" signifies that solutes such as drug molecules with diverse properties can be handled. In our view, the mechanism of the multidrug efflux is not chemically specific but rather has to be based on a physical factor. In earlier works, we showed that the spatial distribution of the solute-vessel potential of mean force (PMF) induced by the solvent plays imperative roles in the insertion∕release process. The PMF can be decomposed into the energetic and entropic components. The entropic component, which originates from the translational displacement of solvent molecules, is rather insensitive to the solute-solvent and vessel inner surface-solvent affinities. This feature is not shared with the energetic component. When the vessel inner surface is neither solvophobic nor solvophilic, the solvents within the vessel cavity and in the bulk offer almost the same environment to any solute with solvophobicity or solvophilicity, and the energetic component becomes much smaller than the entropic component (i.e., the latter predominates over the former). Our idea is that the multidrug efflux can be realized if the insertion∕release process is accomplished by the entropic component exhibiting the insensitivity to the solute properties. However, we have recently argued that the entropic release of the solute is not feasible as long as the vessel geometry is fixed. Here we consider a model of TolC, a cylindrical vessel possessing an entrance at one end and an exit at the other end for the solute. The spatial distribution of the PMF is calculated by employing the three-dimensional integral equation theory with rigid-body models in which the constituents interact only through hard-body potentials. Since the behavior of these models is purely entropic in origin, our analysis is focused on the entropic component. We show that the entropically inserted solute can be released by a continuous variation of the vessel geometry which forms a time-dependent entropic force continuing to accelerate the solute motion to the exit. Solutes with a wide range of sizes are entropically released using the same vessel-geometry variation. The results obtained are fairly general and also applicable to the efflux pump protein AcrB and ATP-binding cassette transporter

Entropic release of a big sphere from a cylindrical vessel

Insertion and release of a solute into and from a cylindrical vessel comprising biopolymers is a fundamental function in biological systems. In earlier works, we reported that the solvent-entropy (SE) effect plays imperative roles for insertion. Here we show that release is also achievable by the SE effect: the solute can be moved from an entrance at one end of the vessel to an exit at the other end using a continuous variation of the vessel geometry. Since the SE effect is rather insensitive to the solute–solvent affinity, our result may provide a clue to the ‘multidrug efflux’ of TolC

Adsorption and Desorption Mechanisms of Rare Earth Elements (REEs) by Layered Double Hydroxide (LDH) Modified with Chelating Agents

In order to obtain the adsorption mechanism and adsorption structures of Rare Earth Elements (REEs) ions adsorbed onto layered double hydroxides (LDH), the adsorption performance of LDH and ethylenediaminetetraacetic acid (EDTA) intercalated LDH for REEs was investigated by batch experiments and regeneration studies. In addition to adsorption capacity, the partition coefficient (PC) was also evaluated to assess their true performance metrics. The adsorption capacity of LDH increases from 24.9 μg·g−1 to 145 μg·g−1 for Eu, and from 20.8 μg·g−1 to 124 μg·g−1 for La by intercalating EDTA in this work; and PC increases from 45.5 μg·g−1·uM−1 to 834 μg·g−1·uM−1 for Eu, and from 33.6 μg·g−1·μM−1 to 405 μg·g−1·μM−1 for La. Comparison of the data indicates that the adsorption affinity of EDTA-intercalated LDH is better than that of precursor LDH no matter whether the concept of adsorption capacity or that of the PC was used. The prepared adsorbent was characterized by XRD, SEM-EDS and FT-IR techniques. Moreover, quantum chemistry calculations were also performed using the GAUSSIAN09 program package. In this calculation, the molecular locally stable state structures were optimized by density functional theory (DFT). Both the quantum chemistry calculations and the experimental data showed that REEs ions adsorbed by EDTA-intercalated LDH are more stable than those adsorbed by precursor LDH. Furthermore, the calculation results of adsorption and desorption rates show that adsorption rates are larger for Eu(III) than for La(III), which agrees with the experimental result that Eu(III) has a higher adsorption ability under the same conditions. The LDHs synthesized in this work have a high affinity for removing REEs ions

Evaluation of the Effect of Patient Education and Strengthening Exercise Therapy Using a Mobile Messaging App on Work Productivity in Japanese Patients With Chronic Low Back Pain: Open-Label, Randomized, Parallel-Group Trial

BackgroundArtificial intelligence–assisted interactive health promotion systems are useful tools for the management of musculoskeletal conditions. ObjectiveThis study aimed to explore the effects of web-based video patient education and strengthening exercise therapy, using a mobile messaging app, on work productivity and pain in patients with chronic low back pain (CLBP) receiving pharmacological treatment. MethodsPatients with CLBP were randomly allocated to either the exercise group, who received education and exercise therapy using a mobile messaging app, or the conventional group. For patient education, a web-based video program was used to provide evidence-based thinking regarding the importance of a cognitive behavioral approach for CLBP. The exercise therapy was developed in accordance with the recommendations for alignment, core muscles, and endogenous activation, including improvement of posture and mobility for proper alignment, stimulation and/or strengthening of deep muscles for spinal stability, and operation of intrinsic pain for the activation of endogenous substances by aerobic exercise. Both groups continued to receive the usual medical care with pharmacological treatment. The end points were changes in work productivity, pain intensity, quality of life, fear of movement, and depression. The observation period for this study was 12 weeks. An analysis adjusted for baseline values, age at the time of consent acquisition, sex, and willingness to strengthen the exercise therapy was performed. ResultsThe exercise and conventional groups included 48 and 51 patients, with a mean age of 47.9 years (SD 10.2 years; n=27, 56.3% male patients) and 46.9 years (SD 12.3 years; n=28, 54.9% male patients) in the full analysis set, respectively. No significant impact of these interventions on work productivity was observed in the exercise group compared with the conventional group (primary end point: Quantity and Quality method; 0.062 vs 0.114; difference between groups −0.053, 95% CI −0.184 to 0.079; P=.43). However, the exercise group showed consistently better trends for the other end points than did the conventional group. Compared with the conventional group, the exercise group showed a significant improvement in the symptoms of low back pain (3.2 vs 3.8; difference between groups −0.5, 95% CI −1.1 to 0.0; P=.04), quality of life (EuroQoL 5 Dimensions 5 Level: 0.068 vs 0.006; difference between groups 0.061, 95% CI 0.008 to 0.114; P=.03), and fear of movement at week 12 (−2.3 vs 0.5; difference between groups −2.8, 95% CI −5.5 to −0.1; P=.04). ConclusionsThis study suggests that patient education and strengthening exercise therapy using a mobile messaging app may be useful for treating CLBP. This study does not reveal the effect of therapeutic interventions on CLBP on work productivity. Thus, further research is required to assess work productivity with therapeutic interventions. Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000041037; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R00004686