NMR-Guided Repositioning of Non-Steroidal Anti-Inflammatory Drugs into Tight Junction Modulators

Bioavailability is a major bottleneck in the clinical application of medium molecular weight therapeutics, including protein and peptide drugs. Paracellular transport of these molecules is hampered by intercellular tight junction (TJ) complexes. Therefore, safe chemical regulators for TJ loosening are desired. Here, we showed a potential application of select non-steroidal anti-inflammatory drugs (NSAIDs) as TJ modulators. Based on our previous observation that diclofenac and flufenamic acid directly bound various PDZ domains with a broad specificity, we applied solution nuclear magnetic resonance techniques to examine the interaction of other NSAIDs and the first PDZ domain (PDZ1) of zonula occludens (ZO)-1, ZO-1(PDZ1). Inhibition of ZO-1(PDZ1) is expected to provide loosening of the epithelial barrier function because the domain plays a crucial role in maintaining TJ integrity. Accordingly, diclofenac and indomethacin were found to decrease the subcellular localization of claudin (CLD)-2 but not occludin and ZO-1 at the apicolateral intercellular compartment of Madin–Darby canine kidney (MDCK) II cells. These NSAIDs exhibited 125–155% improved paracellular efflux of fluorescein isothiocyanate insulin for the Caco-2 cell monolayer. We propose that these NSAIDs can be repurposed as drug absorption enhancers for peptide drugs.     

Ligand-Installed Nanocarriers toward Precision Therapy

Development of drug-delivery systems that selectively target neoplastic cells has been a major goal of nanomedicine. One major strategy for achieving this milestone is to install ligands on the surface of nanocarriers to enhance delivery to target tissues, as well as to enhance internalization of nanocarriers by target cells, which improves accuracy, efficacy, and ultimately enhances patient outcomes. Herein, recent advances regarding the development of ligand-installed nanocarriers are introduced and the effect of their design on biological performance is discussed. Besides academic achievements, progress on ligand-installed nanocarriers in clinical trials is presented, along with the challenges faced by these formulations. Lastly, the future perspectives of ligand-installed nanocarriers are discussed, with particular emphasis on their potential for emerging precision therapies.     

The lubrication mechanism in low speed plastic deformation with a synthetic lubricant — infiltration of lubricant into the boundary contact region

To investigate and evaluate the micro-pool mechanism in a mixed lubrication regime using polybutene lubricants, experiments were performed using 1 mm brass sheet, for various surface rough nesses of a work piece and die, lubricant viscosities and extrusion speeds. Systematic study showed that (1) the lower viscosity lubricant is easily squeezed out from the micro-pools into the flat are a through the troughs between the tool and work piece caused by plastic deformation of work piece, and (2) with decrease in lubricant viscosity and speed, or the larger the tool surface roughness becomes, the more lubricant infiltrates into the tool-work piece interface, which reduces the actual friction coefficient.     

Dynamic Control of a Self-Controlled Synchronous Motor Drive System

Dynamic performance of a speed control system containing a self-controlled synchronous motor is analyzed in detail. It is shown that a field voltage control combined with a margin angle control secures safe commutation of the inverter during transients that cause a large variation in the dc link current and that a current limiter enables the motor speed to change almost linearly at a maximum torque. A simple and efficient control strategy for a fast speed response without an overshoot is then proposed, and the effectiveness of this proposed control as well as the field voltage and margin angle controls is confirmed by experimental investigation.     

A flow method with photocatalytic oxidation of dissolved organic matter using a solid-phase (TiO2) reactor followed by amperometric detection of consumed oxygen

A photocatalytic sensor for the determination of chemical oxygen demand (COD) using titanium dioxide, based on the use of a pair of oxygen electrodes and flow injection analysis, is described. The measuring principle is based on the direct determination of the oxygen concentration change resulting from photocataltic oxidation of organic compounds. One of the two oxygen electrodes, the reference oxygen electrode, was utilized to measure the reference signal responding only to oxygen present in the injected samples. Oxygen consumption due to the TiO2-catalyzed photochemical oxidation of organic compounds in samples was monitored with the working oxygen electrode. The COD value of this sensor was calculated as the difference of the currents at reference and working oxygen electrodes, respectively. The operation characteristics of the sensor are demonstrated using artificially treated wastewater as a substrate. The sensor was also applied to the determination of COD in real water samples from dam reservoirs (n = 20) all over Japan. The results were in good agreement with those from the conventional COD methods (i.e., permanganate and dichromate methods).     

A current-type PWM rectifier with active damping function

A new control method for current-type pulse-width modulation (PWM) rectifiers which can provide active damping function is presented. This damping function is effective only on the harmonic components of AC input current selectively. Thus steady-state waveform distortion and transient oscillation of the input current are reduced by the active damping effects. The active damping function can be realized by feedback control of an LC filter connected to the AC side of the rectifier, and it does not require any additional components in the main circuits, permitting a simple circuit configuration. The control system of the proposed PWM rectifier is analyzed by using a simple block diagram developed in the present paper. From the analytical results, the influence of the circuit parameters and control delay on the active damping effects and the stability of the operation are clarified to establish the design method. To confirm the effectiveness of the active damping function, some results of basic experiments are included. As an example of application of the active damping function, the proposed rectifier is applied to reduce the harmonic currents generated by conventional rectifiers operating in parallel with the proposed rectifier. Some experimental results in this application are also included     

Loss factors of mirrors for a gravitational wave antenna

Low-loss mirrors fabricated by ion-beam-sputtering machines for possible application in an interferometric gravitational wave antenna were evaluated by use of Nd:YAG laser light (lambda = 1064 nm) with two distinct measurements: a tabletop experiment that used a short cavity with a small beam with a beam waist of approximately 2w(0) = 0.82 mm, and an optical test that used a 20-m prototypical gravitational-wave detector with a large beam with a beam waist of approximately 2w(0) = 4.4 mm. A multilayer coating comprised 29 layers of SiO(2)/Ta(2)O(5) and one protective coating of SiO(2). The best values obtained as a result of these measurements were 16 ppm (parts in 10(6)) and 30 ppm in total loss, respectively. Also, a two-dimensional loss map generated by use of a small beam successfully revealed the existence of a loss structure within the coating surface. These results imply that a high-reflectance multilayer coating has some inhomogeneities and a loss distribution with a typical scale of a few millimeters and that the total measured losses depend on the beam spot size.     

Enhancement of serotonergic neural activity contributes to cyclosporine-induced tremors in mice

Patients suffering from inflammatory or dysimmunitary diseases may develop various clinical responses to corticotherapy. This brief article describes the various cellular and molecular mechanisms which underly the genetic, endocrine and immunitary factors involved in corticosensitivity, corticoresistance and corticodependence.     

Life satisfaction and its related factors among institutionalized patients at a Hansen's disease sanatorium

We conducted a questionnaire survey on life styles and health status for 293 patients with Hansen's disease. They were admitted to the wards for disabled and physically able patients of Ohshima Seishoen, in Kagawa prefecture, in 1991. This institution is one of Japan's national leprosy sanitarians. We measured patients' life satisfaction with the Delighted-Terrible Scale. In this report, the distribution of life satisfaction and its associated factors were examined for 210(71.7%) respondents. Factors examined were length of treatment, physical health, and social aspects of life at the sanatorium. The major findings were as follows; 1. The patients aged under 60 had lower proportions of being satisfied with life than those aged 60 or older. The proportions of life satisfaction of the 40-59 age group were 17% for men and 22% for women, while for the 60 or older age groups were 33-44% for men and 41-45% for women. The proportions of life satisfaction in the 60 or older age groups were lower than those of community dwelling elderly persons. 2. We examined factors associated with life satisfaction for the respondents aged 60 or older. Dependence on activities of daily living (ADL) was associated with life satisfaction in some ADL items. Care and aid provided by the staff of the sanatorium may modify the relationship between ADL impairment and life satisfaction. For social aspects of life at the sanatorium, both having networks with family members and having resources other than family were associated with life satisfaction. Going out and positively spending their daily lives were associated with life satisfaction, too. These associations were significant for men. Similar patterns of association were observed for women, but were insignificant. This finding suggests that it is important for the health and medical care staff to pay attention to the social aspects of the life of elderly patients with Hansen's disease.